62 results on '"Ajay Madan"'
Search Results
2. PSUN304 CRN04777 an Oral, Nonpeptide SST5-selective Somatostatin Agonist Dose Dependently Suppresses Basal and Stimulated Insulin Secretion
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Christine Ferrara-Cook, Rosa Luo, Eduardo De La Torre, Yang Wang, Stephen Betz, Ajay Madan, Scott Struthers, Ulrike Hövelmann, Tim Heise, and Alan Krasner
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Endocrinology, Diabetes and Metabolism - Abstract
Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in neonates, infants, and children, and is caused by genetic mutations in the insulin secretion pathway in pancreatic beta-cells. Current medical and surgical treatments are often highly burdensome, only partially effective, and associated with significant morbidity. CRN04777 is a potent orally bioavailable SST5 agonist (EC50=0.41 nM) that is >1300 fold selective over other SST receptor subtypes. CRN04777 has been shown to suppress both glucose- and sulfonylurea (SU)-induced insulin secretion in rats. The latter is a model for the most common known monogenic form of human congenital HI. We report initial results from a randomized, double-blinded, placebo-controlled single ascending dose study evaluating the safety, pharmacokinetics and pharmacodynamics of CRN04777 in 74 healthy volunteers. Endogenous insulin secretion was stimulated using intravenous glucose tolerance tests (IVGTT) or SU challenges in separate cohorts of volunteers. In the IVGTT cohorts, single doses of CRN04777 (0.5-120 mg) were administered after an overnight fast and 1 hour prior to an IV bolus of 300 mg/kg glucose, followed by serial measurements of blood glucose and insulin over 180 minutes. The SU-challenge cohorts received single doses of CRN04777 (30 and 60 mg) one hour after SU administration (5 mg of glibenclamide/glyburide), followed by measurement of the IV glucose infusion rate (GIR) over 8 hours under automated euglycemic clamp conditions (ClampArt®). CRN04777 was orally absorbed (Tmax 1-3 hours) and demonstrated a dose dependent increase in systemic exposures with an apparent terminal elimination t1/2 of approximately 40 hours. Basal insulin secretion was reduced dose-dependently, with a 73% reduction following 120 mg of CRN04777. Likewise, glucose stimulated insulin secretion during the IVGTT (plasma insulin AUC) was reduced dose-dependently by approximately 50% with a parallel doubling of plasma glucose AUC following 120 mg of CRN04777. CRN04777 resulted in dose-dependent reversal of SU-induced insulin secretion, with 79% and 90% reductions in insulin AUC5-180min, respectively, at 30 and 60 mg doses. At the 60 mg dose of CRN04777, no exogenous glucose infusion was needed to prevent SU-induced hypoglycemia. CRN04777 was well tolerated across the dose range evaluated. All adverse events (AEs) were considered mild or moderate and there were no serious AEs. The data from this single-dose, proof-of-concept study show that the selective SST5 agonist CRN04777 is well tolerated after oral administration in healthy volunteers, is suitable for once daily dosing and suppresses insulin secretion under basal and stimulated conditions, including in a pharmacologic model of congenital HI. Multiple ascending dose evaluations in healthy volunteers are underway to support future studies in congenital HI patients. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.
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- 2022
3. ACROBAT Edge: Safety and efficacy of switching injected SRLs to oral paltusotine in patients with acromegaly
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Monica R Gadelha, Murray B Gordon, Mirjana Doknic, Emese Mezősi, Miklós Tóth, Harpal Randeva, Tonya Marmon, Theresa Jochelson, Rosa Luo, Michael Monahan, Ajay Madan, Christine Ferrara-Cook, R Scott Struthers, and Alan Krasner
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Endocrinology ,Endocrinology, Diabetes and Metabolism ,Biochemistry (medical) ,Clinical Biochemistry ,Biochemistry - Abstract
Context Paltusotine is a once-daily, oral, nonpeptide small-molecule somatostatin receptor type 2 (SST2) agonist in clinical development for treatment of acromegaly. Objective This work aimed to evaluate change in insulin-like growth factor I (IGF-I) levels in patients switched from octreotide long-acting release or lanreotide depot monotherapy to paltusotine. Methods A phase 2, open-label, prospective, multicenter, multinational, nonrandomized, single-arm exploratory study was conducted in which dosage uptitrations were performed in a double-blinded manner. At 26 global sites, patients with acromegaly switched to paltusotine from injected somatostatin receptor ligand (SRL)-based therapy. Patients received 13-week treatment with once-daily oral paltusotine (10-40 mg/d). The primary end point was change from baseline to week 13 in IGF-I for patients who switched from long-acting octreotide or lanreotide depot monotherapy to paltusotine (group 1). All patients underwent a 4-week paltusotine washout at end of treatment period (wk 13-17). IGF-I, growth hormone (GH), patient-reported outcome, and safety data were collected. Results Forty-seven patients enrolled. In group 1 (n = 25), IGF-I and GH showed no significant change between SRL baseline and end of paltusotine treatment at week 13 (median change in IGF-I = −0.03×upper limit of normal [ULN]; P = .6285; GH = −0.05 ng/mL; P = .6285). IGF-I and GH rose significantly in the 4 weeks after withdrawing paltusotine (median change in IGF-I = 0.55×ULN; P < .0001 [median increase 39%]; GH = 0.72 ng/mL; P < .0001 [109.1% increase]). No patients discontinued because of adverse events (AE); no treatment-related serious AEs were reported. Conclusion These results suggest once-daily oral paltusotine was effective in maintaining IGF-I values in patients with acromegaly who switched from injected SRLs. Paltusotine was well tolerated with a safety profile consistent with other SRLs.
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- 2022
4. Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers
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Ajay Madan, Stacy Markison, Stephen F. Betz, Alan Krasner, Rosa Luo, Theresa Jochelson, Jason Lickliter, and R. Scott Struthers
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Male ,Endocrinology ,Double-Blind Method ,Human Growth Hormone ,Endocrinology, Diabetes and Metabolism ,Growth Hormone ,Acromegaly ,Humans ,Insulin-Like Growth Factor I ,Healthy Volunteers - Abstract
Purpose Evaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors. Methods A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability. Results Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo. Conclusions Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors. Trial registration NCT03276858, registered September 8, 2017, retrospectively registered.
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- 2021
5. OR12-2 Inhibition of Basal and ACTH-stimulated Cortisol Secretion in Humans Using an Oral Nonpeptide ACTH Antagonist (CRN04894)
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Stephen Betz, Christine Ferrara-Cook, Martha Hernandez-Illas, Rosa Luo, Ajay Madan, Stephanie Miller, Scott Struthers, Peter Trainer, Yang Wang, and Alan Krasner
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Endocrinology, Diabetes and Metabolism - Abstract
CRN04894 is a potent orally bioavailable MC2R (adrenal cortex specific ACTH receptor) antagonist (Kb=0.34 nM) that is >1000-fold selective for MC2R over other melanocortin receptor subtypes. In rats receiving continuous administration of ACTH via subcutaneously implanted osmotic pumps, oral administration of CRN04894 over 7 days has previously been shown to result in dose-dependent suppression of basal and ACTH stimulated corticosterone levels. This compound is in clinical development for the treatment of diseases of ACTH excess including congenital adrenal hyperplasia (CAH) and Cushing's Disease. We report initial results from a randomized double-blinded, placebo-controlled single ascending dose study evaluating the safety, pharmacokinetics and pharmacodynamics of CRN04894 in 39 healthy volunteers. After an overnight fast, single doses of CRN04894 were administered at approximately 8 am, 2 hours prior to an IV bolus of ACTH 1-24 (cosyntropin). Serial cortisol over 600 minutes and pharmacokinetics over 168 hours post CRN04894 dose were measured. Two different challenge doses of ACTH 1-24 were studied: 250 μg (supra-pharmacological) and 1 μg (comparable to ACTH concentrations encountered in CAH and Cushing's Disease). CRN04894 was rapidly orally absorbed (median tmax 0.5-1.5 hour), and demonstrated a dose dependent increase in systemic exposure, with an apparent terminal elimination t1/2 of approximately 20 hours. Unstimulated (basal) cortisol measured 2 hours after CRN04894 administration fell in a dose-dependent manner, resulting in reduction near the theoretical maximum with the 80 mg dose cohort (-56.1% [SEM 4.0%, n=12] vs +17.4% in placebo [SEM=18.1%, n=9]). Dose-dependent cortisol suppression following a supra-pharmacological ACTH-stimulated (250 μg) was also observed, with a 41% reduction in the area under the curve (AUC60-600min) post-stimulation at the 80 mg dose. Furthermore, a single dose of 80 mg of CRN04894 reduced the cortisol response (AUC15-120 min) to a disease relevant 1 μg ACTH challenge by 48%, maintaining cortisol concentrations within the normal range seen prior to dosing in a basal unstimulated state. Single doses of CRN04894 were well tolerated with no need for glucocorticoid supplementation. All adverse events (AEs) were considered mild or moderate and there were no serious AEs. The data from this single-dose, proof-of-concept study show that MC2R antagonist CRN04894 was well tolerated after oral delivery in healthy volunteers and demonstrated dose-dependent increases in exposure with lowering of basal and ACTH-stimulated cortisol secretion, including in the presence of disease relevant excess ACTH exposure. Multiple ascending dose evaluations are underway in anticipation of studies in patients with diseases of ACTH excess. Presentation: Sunday, June 12, 2022 11:15 a.m. - 11:30 a.m.
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- 2022
6. ACROBAT Advance: progress report on a study of long-term safety and efficacy of paltusotine for the treatment of acromegaly
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Struthers R. Scott, Murray B. Gordon, Alan Krasner, Rosa Luo, Miklós Tóth, Emese Mezosi, Alessandra Casagrande, Cesar Boguszewski, Mirjana Doknic, Harpal S. Randeva, Gadelha Monica R, Melissa Nichols, Theresa Jochelson, Christine Ferrara-Cook, and Ajay Madan
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medicine.medical_specialty ,business.industry ,Acromegaly ,Medicine ,Long term safety ,business ,Intensive care medicine ,medicine.disease - Published
- 2021
7. Identification of a dose range for once daily oral paltusotine in patients with acromegaly that maintains IGF-1 levels when switching from long-acting somatostatin receptor ligand therapy
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Rosa Luo, Mirjana Doknic, Mônica R. Gadelha, Harpal S. Randeva, Miklos Toth, Tonya Marmon, Alan Krasner, Ajay Madan, Murray B. Gordon, Michael Monahan, Scott Struthers, and Emese Mezosi
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medicine.medical_specialty ,Endocrinology ,Long acting ,Somatostatin receptor ligand ,business.industry ,Range (biology) ,Internal medicine ,Acromegaly ,medicine ,In patient ,Once daily ,medicine.disease ,business - Published
- 2021
8. Effects of nonpeptide orally bioavailable ACTH antagonists on adrenal gland size and function in rats
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R. Scott Struthers, Stephen F. Betz, Taylor Kredel, Shirley Cruz, Melissa Fowler, Michael Johns, Jon Athanacio, Agnes Antwan, Stacy Markison, Ajay Madan, Greg J. Reinhart, Oleg Tsivkovski, Ana Karin Kusnetzow, and Rosa Luo
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medicine.medical_specialty ,Endocrinology ,medicine.anatomical_structure ,Chemistry ,Adrenal gland ,Internal medicine ,medicine ,Function (biology) ,Bioavailability - Published
- 2020
9. Absolute oral bioavailability and absorption, metabolism, excretion of [14C]-Labeled paltusotine (CRN00808), an orally bioavailable, nonpeptide, selective, somatostatin receptor 2 (sst2) biased agonist for the treatment of acromegaly
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Rosa Luo, Marle Sjoerd van, Struthers R. Scott, Ajay Madan, Alan Krasner, and Chris Ferrara-Cook
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Excretion ,Agonist ,medicine.drug_class ,Chemistry ,Acromegaly ,medicine ,Somatostatin receptor 2 ,Absorption (skin) ,Metabolism ,Pharmacology ,medicine.disease ,Bioavailability - Published
- 2020
10. Safety and IGF-1 levels with once daily oral sst2 agonist paltusotine (CRN00808) in acromegaly patients previously treated with peptide long-acting somatostatin receptor ligands: Initial data from the open label ACROBAT Edge phase 2 study
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Struthers R. Scott, Murray B. Gordon, Alan Krasner, Harpal S. Randeva, Michael Monahan, Tonya Marmon, Ajay Madan, Emese Mezosi, Rosa Luo, Chris Ferrara-Cook, Kim Fowler, Miklós Tóth, and Mirjana Doknic
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Agonist ,chemistry.chemical_classification ,medicine.medical_specialty ,medicine.drug_class ,Chemistry ,Somatostatin receptor ,Phases of clinical research ,Peptide ,medicine.disease ,Long acting ,Endocrinology ,Internal medicine ,Acromegaly ,medicine ,Open label ,Previously treated - Published
- 2020
11. MON-089 Discovery and Identification of Late Stage Selective Nonpeptide Somatostatin Subtype 5 (sst5) Agonists for the Treatment of Hyperinsulinemic Hypoglycemia
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Rosa Luo, Ana Karin Kusnetzow, Stacy Markison, Stephen F. Betz, Agnes Antwan, Michael Johns, Oleg Tsivkovski, Rosalia de Necochea-Campion, Yun Fei Zhu, Scott Struthers, Melissa Fowler, Shmiao Wang, Jon Athanacio, Ajay Madan, Elizabeth Rico, Emmanuel Sturchler, Taylor Kredel, and Jian Zhao
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medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Late stage ,medicine.disease_cause ,Endocrinology ,Somatostatin ,Pediatric Endocrinology ,Internal medicine ,medicine ,Identification (biology) ,Pediatric Obesity, Thyroid, and Cancer ,business ,Hyperinsulinemic hypoglycemia ,AcademicSubjects/MED00250 - Abstract
Congenital hyperinsulinism (CHI) results from mutations within the insulin secretion pathway and is characterized by excessive and/or inappropriate insulin secretion by pancreatic islet β-cells. CHI is the most common cause of persistent hypoglycemia in newborns and infants and is estimated to affect 1:2500 to 1:50,000 live births. Prompt recognition and treatment are vital to prevent coma, long-term neurological complications, and even death. If medical control of CHI is unsuccessful, a near-total pancreatectomy may be required, but hypoglycemia often persists. The neuropeptide somatostatin is an important modulator of pancreatic hormonal signaling and activity at different somatostatin receptor (sst) subtypes dictates the suppression of insulin and/or glucagon. The injectable peptide drugs octreotide and lanreotide are potent sst2 agonists used to treat CHI, but in addition to suppressing insulin, the sst2 activity of these peptides may also inhibit glucagon secretion, potentially reducing effectiveness and compromising a key defense against hypoglycemia. Glucagon secretion from α-cells is inhibited through activation of sst2 receptors, while insulin secretion from β-cells is inhibited through activation of sst2 and sst5. We therefore hypothesize that agonists selectively targeting sst5 and lacking sst2 activity will offer an improved efficacy/safety profile for patients with hyperinsulinemic hypoglycemia. Using iterative medicinal chemistry and pharmacology, Crinetics has discovered several classes of highly potent, orally bioavailable, small molecule sst-subtype selective agonists with drug-like pharmaceutical properties. Our discovery efforts aimed at finding a compound to treat CHI have yielded potent and selective nonpeptide sst5 agonists with sub-nanomolar EC50s in cell-based assays of receptor activation. Insulin secretion from isolated human and rat islets was suppressed upon exposure to sst5 agonists. Potent and selective sst5 agonists were then evaluated in a number acute and repeat dose in vivo models (e.g., oGTT, fed/fasted conditions, sulfonylurea-induced hypoglycemia) to assess physiological effects and to gain mechanistic insights. As predicted by the in vitro pharmacology, selective nonpeptide sst5 agonists suppressed insulin secretion and raised blood glucose levels in each model, while having minimal effects on glucagon secretion. Leading sst5 agonists were also evaluated for drug like characteristics, including stability in liver microsomes, lack of inhibition of cytochromes P450 and the hERG ion channel, and were shown to exhibit good exposure upon oral dosing in both rats and dogs. The culmination of these studies has led to a subset of candidate molecules that are being evaluated in genotoxicity, safety pharmacology, and general toxicity studies to determine the molecule most suitable for evaluation in human clinical trials.
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- 2020
12. OR23-05 Human Absorption, Metabolism, Excretion, and Absolute Oral Bioavailability of 14C-CRN00808, an Orally Bioavailable, Nonpeptide, Selective, Somatostatin Receptor 2 (sST2) Biased Agonist for the Treatment of Acromegaly
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Rosa Luo, Alan Krasner, Stephen Ferrara Cook, Ajay Madan, Scott Struthers, and Sjoerd van Marle
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Agonist ,medicine.drug_class ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Metabolism ,Absorption (skin) ,Pharmacology ,medicine.disease ,Bioavailability ,Excretion ,Neuroendocrinology and Pituitary ,Acromegaly ,medicine ,Somatostatin receptor 2 ,Pituitary Tumors: Trials and Studies ,AcademicSubjects/MED00250 - Abstract
Injected depot formulations of somatostatin peptide analogs are routinely used to treat acromegaly and neuroendocrine tumors (NETs). CRN00808, a small molecule nonpeptide selective somatostatin receptor 2 (sst2) agonist, is being evaluated for efficacy and safety in patients with acromegaly. The current Phase 1 study was conducted in two Parts: In Part A, the absorption, metabolism, excretion, and mass balance of a single oral dose of 20 mg [14C]-CRN00808 (3.0 MBq) oral solution was characterized in six healthy male subjects. Plasma, blood, urine, and feces were collected for up to 432 hours, and were analyzed for total radioactivity and CRN00808 concentrations (plasma only). Metabolite profiling was conducted on the plasma, urine, and feces samples. In Part B, the absolute bioavailability of CRN00808 was determined by administering a single oral dose of 20 mg CRN00808 compared with a single micro-tracer intravenous (IV) bolus injection of 50 µg [14C]-CRN00808 (0.0185 MBq) in five healthy male subjects. The IV dose was administered approximately 90 minutes after the oral dose. Plasma samples were collected for up to 144 hours and were analyzed for total radioactivity and CRN00808 concentrations (plasma only). Key data from Part A and Part B will be presented. Available data from Part A of the study show that >90% of radioactivity was recovered within 7 days of dosing. The primary route of excretion was the feces (>90%) with minimal excretion in the urine (
- Published
- 2020
13. COVID-19: A gender-biased pandemic
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Pulin Saluja, Ridhima Singh, and Ajay Madan
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Otorhinolaryngology ,General Dentistry ,Pathology and Forensic Medicine - Published
- 2022
14. Pharmacokinetics and Safety of an Improved Oral Formulation of Paltusotine, a Selective, Non-Peptide Somatostatin Receptor 2 (SST2) Agonist for the Treatment of Acromegaly
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Cosina Mui, Rosa Luo, Sepehr Shakib, Ajay Madan, Gerald Burke, Alan Krasner, and Christine Ferrara-Cook
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Agonist ,Pharmacokinetics ,business.industry ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Acromegaly ,medicine ,Somatostatin receptor 2 ,Pharmacology ,medicine.disease ,business ,Non peptide - Abstract
Depot injection formulations of peptide somatostatin receptor ligands (SRLs) are routinely used to treat acromegaly and neuroendocrine tumors (NETs). Paltusotine (CRN00808), an orally administered small molecule nonpeptide selective somatostatin receptor 2 (SST2) agonist has been shown to maintain GH and IGF-1 levels in acromegaly patients previously on depot SRLs (ACROBAT Edge NCT03789656). In this study, a capsule formulation was used, which did not exhibit dose proportional pharmacokinetics (PK) at doses >40 mg, required a 2-hour post-dose fast in overnight fasted patients, and had the potential for reduced bioavailability when taken with proton-pump inhibitors (PPI). A spray-dried dispersion (SDD) tablet formulation was developed with improved solubility in the physiological pH range and its performance was evaluated in healthy volunteers. Male and female healthy volunteers who met inclusion/exclusion criteria were enrolled in a single-center Phase 1 study (ANZCTR registration ACTRN12619001562167). A Cohort of 12 subjects was administered a single dose of paltusotine in a four-period cross-over design. Periods 1 and 2 assessed the effect of lansoprazole (a PPI) on PK of 20 mg dose of paltusotine SDD tablets. In Period 3, 20 mg dose of paltusotine SDD tablets was co-administered with a high fat, high-calorie meal. In Period 4, a 60 mg dose of paltusotine SDD tablets was administered to assess dose proportionality. In a separate cohort of subjects (n=12; also, a 4-period cross-over design), the relative bioavailability of capsules and SDD tablets was assessed, and the effect of food administration 0.5, 1, and 2 hour post-dose was evaluated. Subsequently, in another cohort of 12 subjects (a 3-period cross-over design), dose proportionality of the SDD tablets was evaluated at 40 mg and 80 mg dose with a 1-hour post-dose fast. A 4 hours post-dose fast was also assessed for the 80 mg dose. Pharmacokinetics and safety of paltusotine were evaluated. Paltusotine was generally well tolerated in this study. SDD tablets exhibited dose proportional increase in total systemic exposure (AUC) up to a dose of 80 mg. Healthy volunteers pretreated with the PPI, lansoprazole (15 mg bid for 3 days), and co-administered with paltusotine SDD tablets exhibited a small decrease (approximately 25%) in systemic exposure to paltusotine compared with the same subjects that had washed out from the PPI-pretreatment. SDD tablets exhibited significant reduction in systemic exposure when co-administered with a high-fat, high-calorie meal. However, the SDD formulation was less sensitive to timing of post-dose food administration compared to the capsule formulation. These data suggest that the SDD tablet formulation of paltusotine improves flexibility in dose administration, can be co-administered with PPIs and other agents that increase stomach pH, and reduces the post-dose fasting requirement.
- Published
- 2021
15. SAT-364 Nonpeptide Orally-Bioavailable ACTH Antagonists: Suppression of ACTH-Induced Corticosterone Secretion and Adrenal Hypertrophy in Rats
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Ana Karin Kusnetzow, Scott Struthers, Michael Johns, Julie Nguyen, Elizabeth Rico-Bautista, Taylor Kredel, Rosa Luo, Yun Fei Zhu, Stacy Markison, Melissa Fowler, Stephen F. Betz, Greg J. Reinhart, Sun Hee Kim, Christine Staley, Sangdon Han, Hannah Tan, Jon Athanacio, and Ajay Madan
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medicine.medical_specialty ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Corticosterone ,Adrenal hypertrophy ,Endocrinology, Diabetes and Metabolism ,Internal medicine ,medicine ,Secretion ,Adrenal ,Adrenal Basic and Translational ,Bioavailability - Abstract
Cushing’s disease is most commonly the result of a microadenoma derived from pituitary corticotrophic cells that secretes excess adrenocorticotropic hormone (ACTH). ACTH is an important modulator of steroidal hormone synthesis and secretion from the adrenal gland and its selective activity at the melanocortin type 2 receptor (MC2) dictates the synthesis and secretion of cortisol (corticosterone in rats). The resulting hypercortisolemia in Cushing’s patients presents in a myriad of symptoms that include growth of fat pads, excessive sweating, dilation of capillaries, thinning of the skin, muscle weakness, hirsutism, depression/anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, and heart disease, among others that result in high morbidity. We hypothesize that blocking ACTH action directly via a selective MC2 receptor antagonist may provide an important new therapeutic mechanism to help better manage Cushing’s disease in patients. To test this hypothesis, we launched an iterative medicinal chemistry program to identify potent and selective nonpeptide MC2 receptor antagonists with pharmaceutical and safety characteristics suitable for evaluation in human clinical trials. Unlike most other G protein coupled receptors, MC2 requires the presence of an accessory protein (MRAP) for cell surface expression and recognition of ACTH and our effort led to small molecule nonpeptides with antagonist activity in CHO-K cells stably expressing the MC2-MRAP complex. Iterative optimization led rapidly to the discovery of multiple chemical classes of highly potent, nonpeptide MC2 selective antagonist leads, which were then further optimized for drug-like characteristics. We have identified multiple compounds that exhibit high potency for human and rat MC2 receptors (hMC2 Kb
- Published
- 2019
16. Repercussions of coronavirus outbreak
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Manpreet Arora, Pulin Saluja, Aparna Dave, and Ajay Madan
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Geography ,medicine ,Outbreak ,medicine.disease_cause ,Virology ,Coronavirus - Published
- 2020
17. Role of Cytokeratin-7 in the pathogenesis of odontogenic cysts - an immunohistochemical study
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Manpreet Arora, Ajay Madan, Alpana Katiyar, Charu Khurana, Radhika Rai, Pulin Saluja, Aparna Dave, and Vishwa Prakash Shetty
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Radicular Cyst ,Pathology ,medicine.medical_specialty ,dentigerous cysts ,business.industry ,General Medicine ,cytokeratin-7 ,Epithelium ,Odontogenic ,Staining ,Pathogenesis ,radicular cysts ,Cytokeratin ,stomatognathic diseases ,medicine.anatomical_structure ,odontogenic keratocysts ,immunohistochemistry ,medicine ,Immunohistochemistry ,business ,Pathological ,Original Research ,Dental Medicine - Abstract
Introduction. Odontogenic cysts are distinct entities and quite a common occurrence in the jaw bones. These are individual lesions which arise from the same odontogenic apparatus but with varying pathogenesis. Cytokeratins are integral components in tooth development and are expressed across the odontogenic tissues in physiological and pathological states. Aim. To elucidate the role of cytokeratin-7 in the pathogenesis of odontogenic cysts by immunohistochemistry Method. Cytokeratin-7 (CK-7) was assessed in 39 cases of odontogenic lesions retrieved from the archival files which included 15 cases of Dentigerous cysts (DC), 12 cases of Odontogenic keratocysts (OKC) and 12 cases of Radicular cysts (RC) and also 8 cases of control specimens. Statistical analysis. Results obtained were statistically analyzed using chi-square test to assess the association between different odontogenic cysts used in this study and Cytokeration-7 staining. The difference was considered to be of statistical significance if the p value was ≤ 0.05. Results. CK7 expression was maximum in dentigerous cycts (66.66%) followed by radicular cysts (41.66%) and odontogenic keratocysts (16.6%). On evaluation of staining and expression pattern, highest positivity is shown in Dentigerous cysts and the positivity is seen in suprabasal (60%) and superficial layers (40%) whereas radicular cysts and odontogenic keratocysts showed positivity in superficial and spinous layers. Conclusion. Cytokeratin-7 expression correlates with the degree of differentiation of the epithelium. So the cysts with a well-differentiated epithelium (RC and DC) express CK-7, while the cysts with a less well-differentiated epithelium (OKC) show slight positivity. Thus it can be useful to differentiate OKC from DC and RC.
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- 2018
18. Pharmacologic Characterization of Valbenazine (NBI-98854) and Its Metabolites
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Ajay Madan, Sam R. J. Hoare, Haig Bozigian, Evan Smith, and Dimitri E. Grigoriadis
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Blood Platelets ,medicine.medical_specialty ,Tetrabenazine ,Metabolite ,CHO Cells ,Pharmacology ,Vesicular monoamine transporter 2 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cricetulus ,In vivo ,Dopamine ,Internal medicine ,Cricetinae ,medicine ,Animals ,Humans ,Valbenazine ,biology ,Chemistry ,Valine ,Corpus Striatum ,030227 psychiatry ,Rats ,Monoamine neurotransmitter ,Endocrinology ,HEK293 Cells ,Deutetrabenazine ,Vesicular Monoamine Transport Proteins ,biology.protein ,Molecular Medicine ,030217 neurology & neurosurgery ,medicine.drug ,Protein Binding - Abstract
The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2, is approved for the treatment of tardive dyskinesia. Valbenazine is converted to two significant circulating metabolites in vivo, namely, (+)-α-dihydrotetrabenazine (R,R,R-HTBZ) and a mono-oxy metabolite, NBI-136110. Radioligand-binding studies were conducted to assess and compare valbenazine, tetrabenazine, and their respective metabolites in their abilities to selectively and potently inhibit [3H]-HTBZ binding to VMAT2 in rat striatal, rat forebrain, and human platelet homogenates. A broad panel screen was conducted to evaluate possible off-target interactions of valbenazine, R,R,R-HTBZ, and NBI-136110 at >80 receptor, transporter, and ion channel sites. Radioligand binding showed R,R,R-HTBZ to be a potent VMAT2 inhibitor in homogenates of rat striatum (Ki = 1.0-2.8 nM), rat forebrain (Ki = 4.2 nM), and human platelets (Ki = 2.6-3.3 nM). Valbenazine (Ki = 110-190 nM) and NBI-136110 (Ki = 160-220 nM) also exhibited inhibitory effects on VMAT2, but with lower potency than R,R,R-HTBZ. Neither valbenazine, R,R,R-HTBZ, nor NBI-136110 had significant off-target interactions at serotonin (5-HT1A, 5-HT2A, 5-HT2B) or dopamine (D1 or D2) receptor sites. In vivo studies measuring ptosis and prolactin secretion in the rat confirmed the specific and dose-dependent interactions of tetrabenazine and R,R,R-HTBZ with VMAT2. Evaluations of potency and selectivity of tetrabenazine and its pharmacologically active metabolites were also performed. Overall, the pharmacologic characteristics of valbenazine appear consistent with the favorable efficacy and tolerability findings of recent clinical studies [KINECT 2 (NCT01733121), KINECT 3 (NCT02274558)].
- Published
- 2016
19. Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: Identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H1-antihistamines for insomnia
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Wilna J. Moree, Paul D. Crowe, Jianyun Wen, Siobhan Malany, Fabio C. Tucci, Sam R. J. Hoare, Melissa Arellano, Graham Beaton, Bin-Feng Li, Jinghua Yu, Joe A. Tran, Satheesh B. Ravula, Robert E. Petroski, and Ajay Madan
- Subjects
Benzimidazole ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Heteroatom ,Pharmaceutical Science ,Biochemistry ,Combinatorial chemistry ,Cns penetration ,chemistry.chemical_compound ,Thiomorpholine ,chemistry ,Morpholine ,Drug Discovery ,Molecular Medicine ,Piperidine ,Selectivity ,Molecular Biology ,Lead compound - Abstract
The structure–activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pKa and/or log P of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.
- Published
- 2012
20. Influence of pKa on the biotransformation of indene H1-antihistamines by CYP2D6
- Author
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Paul D. Crowe, Said Zamani-Kord, Bin-Feng Li, Sam R. J. Hoare, Hua Wang, Charles Q. Huang, Siobhan Malany, Wilna J. Moree, Ajay Madan, Fabio C. Tucci, Graham Beaton, Chun Yang, and Jianyun Wen
- Subjects
CYP2D6 ,Primary (chemistry) ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Substituent ,Pharmaceutical Science ,Metabolism ,Biochemistry ,In vitro ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cytochrome P-450 CYP2D6 ,Indenes ,chemistry ,Biotransformation ,Pyrazines ,Drug Discovery ,Histamine H1 Antagonists ,Molecular Medicine ,Moiety ,Receptors, Histamine H1 ,Indene ,Molecular Biology - Abstract
Structure–activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H1-antihistamines. Reductions in pKa via incorporation of a β-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.
- Published
- 2011
21. A pharmacokinetic evaluation of five H1antagonists after an oral and intravenous microdose to human subjects
- Author
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Paul D. Crowe, Robert Farber, R. Colin Garner, Christopher F. O'Brien, Jianyun Wen, B. Oosterhuis, Ajay Madan, Zhihong O’Brien, Graham Lappin, Haig Bozigian, and Graham Beaton
- Subjects
Adult ,Male ,Microdosing ,Cmax ,Administration, Oral ,Pharmacology ,Young Adult ,Pharmacokinetics ,MicroDose ,Oral administration ,medicine ,Humans ,Pharmacology (medical) ,Chromatography, High Pressure Liquid ,Volume of distribution ,Cross-Over Studies ,Dose-Response Relationship, Drug ,business.industry ,Diphenhydramine ,Middle Aged ,Bioavailability ,Injections, Intravenous ,Histamine H1 Antagonists ,business ,medicine.drug - Abstract
AIMS: To evaluate the pharmacokinetics (PK) of five H1 receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg). METHODS: Five H1 receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy. RESULTS: The median clearance (CL), apparent volume of distribution (V d) and apparent terminal elimination half-life (t1/2) of diphenhydramine after an i.v. microdose were 24.7 l h-1, 302 l and 9.3 h, and the oral Cmax and AUC0-� were 0.195 ng ml-1 and 1.52 ng h ml-1, respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2. CONCLUSIONS: Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection. © 2009 Neurocrine Biosciences.
- Published
- 2009
22. Zwitterionic uracil derivatives as potent GnRH receptor antagonists with improved pharmaceutical properties
- Author
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Yongsheng Chen, R. Scott Struthers, Yun-Fei Zhu, Charles Q. Huang, Jenny Wen, Michael S. Brown, Steve F. Betz, Jaimie K. Rueter, Chun Yang, John Saunders, Ajay Madan, Chen Chen, Colin F. Regan, Zhiqiang Guo, Coon Timothy Richard, Wanlong Jiang, and Mi Chen
- Subjects
endocrine system ,Stereochemistry ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Pharmaceutical Science ,Gonadotropin-releasing hormone ,Biochemistry ,Chemical synthesis ,Gonadotropin-Releasing Hormone ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Cytochrome P-450 CYP3A ,Humans ,Uracil ,Molecular Biology ,Ions ,chemistry.chemical_classification ,Unspecific monooxygenase ,Molecular Structure ,biology ,CYP3A4 ,Chemistry ,Organic Chemistry ,Cytochrome P450 ,Stereoisomerism ,Kinetics ,Enzyme ,Models, Chemical ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine ,Peptides ,Receptors, LHRH ,hormones, hormone substitutes, and hormone antagonists - Abstract
A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition.
- Published
- 2008
23. Potent and orally bioavailable zwitterion GnRH antagonists with low CYP3A4 inhibitory activity
- Author
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Warren Wade, Martin W. Rowbottom, Yongsheng Chen, R. Scott Struthers, Haig Bozigian, Qiu Xie, Takung Chen, Fabio C. Tucci, Jenny Wen, Dongpei Wu, Charles Q. Huang, Joseph Pontillo, Zhiqiang Guo, John Saunders, Yun-Fei Zhu, Ajay Madan, and Chen Chen
- Subjects
Stereochemistry ,Carboxylic acid ,Clinical Biochemistry ,Pharmaceutical Science ,Inhibitory postsynaptic potential ,Biochemistry ,Gonadotropin-Releasing Hormone ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Oral administration ,Drug Discovery ,Animals ,Cytochrome P-450 CYP3A ,Humans ,Structure–activity relationship ,Uracil ,Molecular Biology ,chemistry.chemical_classification ,Unspecific monooxygenase ,Molecular Structure ,CYP3A4 ,Chemistry ,Organic Chemistry ,Antagonist ,Haplorhini ,Rats ,Cytochrome P-450 CYP3A Inhibitors ,Molecular Medicine ,Receptors, LHRH - Abstract
Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4.
- Published
- 2008
24. Identification and characterization of pyrrolidine diastereoisomers as potent functional agonists and antagonists of the human melanocortin-4 receptor
- Author
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Joe A. Tran, Melissa Arellano, Stacy Markison, John Saunders, Ajay Madan, Dragan Marinkovic, Chen Chen, Sam R. J. Hoare, Alan C. Foster, Beth A. Fleck, Jenny Wen, Fabio C. Tucci, Caroline W. Chen, and Wanlong Jiang
- Subjects
Male ,Agonist ,Pyrrolidines ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,Biochemistry ,Eating ,Structure-Activity Relationship ,Melanocortin receptor ,Drug Discovery ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,IC50 ,Dose-Response Relationship, Drug ,Chemistry ,Organic Chemistry ,Antagonist ,Stereoisomerism ,Amides ,Rats ,Melanocortin 4 receptor ,Kinetics ,Receptor, Melanocortin, Type 4 ,Molecular Medicine ,Melanocortin - Abstract
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.
- Published
- 2008
25. Design, Synthesis, In Vitro, and In Vivo Characterization of Phenylpiperazines and Pyridinylpiperazines as Potent and Selective Antagonists of the Melanocortin-4 Receptor
- Author
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Stacy Markison, Melissa Arellano, Joe A. Tran, Haig Bozigian, Caroline W. Chen, Wanlong Jiang, John Saunders, Fabio C. Tucci, Beth A. Fleck, Ajay Madan, Daniel Marks, Ta Kung Chen, Chen Chen, Yang Sai, John Harman, Dragan Marinkovic, Alan C. Foster, Jenny Wen, and Sam R. J. Hoare
- Subjects
Male ,Models, Molecular ,Benzylamines ,Cachexia ,Tertiary amine ,Pyridines ,Crystallography, X-Ray ,Piperazines ,Cell Line ,Carcinoma, Lewis Lung ,Eating ,Mice ,Structure-Activity Relationship ,Pharmacokinetics ,In vivo ,Drug Discovery ,Cyclic AMP ,medicine ,Animals ,Humans ,Structure–activity relationship ,Receptor ,Chemistry ,Antagonist ,Stereoisomerism ,medicine.disease ,Amides ,Mice, Inbred C57BL ,Melanocortin 4 receptor ,Biochemistry ,Drug Design ,Receptor, Melanocortin, Type 4 ,Molecular Medicine ,Neoplasm Transplantation - Abstract
Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K(i) value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.
- Published
- 2007
26. Discovery of 1-{2-[(1S)-(3-Dimethylamino-propionyl)amino-2-methylpropyl]-4-methyl-phenyl}-4-[(2R)-methyl-3-(4-chlorophenyl)-propionyl]piperazine as an Orally Active Antagonist of the Melanocortin-4 Receptor for the Potential Treatment of Cachexia
- Author
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Michael Johns, Beth A. Fleck, Ajay Madan, Dragan Marinkovic, Margaret Joppa, Chen Chen, Stacy Markison, Wanlong Jiang, Melissa Arellano, Alan C. Foster, Joe A. Tran, Fabio C. Tucci, Takung Chen, Jenny Wen, Yang Sai, Sam R. J. Hoare, Caroline W. Chen, and John Saunders
- Subjects
Male ,Cachexia ,Stereochemistry ,Administration, Oral ,Biological Availability ,Chemical synthesis ,Piperazines ,Rats, Sprague-Dawley ,Eating ,Mice ,Radioligand Assay ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,Oral administration ,Drug Discovery ,Cyclic AMP ,Animals ,Humans ,Structure–activity relationship ,Chemistry ,Antagonist ,Stereoisomerism ,Neoplasms, Experimental ,Macaca mulatta ,Rats ,Bioavailability ,Mice, Inbred C57BL ,Melanocortin 4 receptor ,Piperazine ,Solubility ,Microsomes, Liver ,beta-Alanine ,Receptor, Melanocortin, Type 4 ,Molecular Medicine ,Melanocortin ,Neoplasm Transplantation - Abstract
A potent and selective antagonist of the melanocortin-4 receptor, 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.
- Published
- 2007
27. Propionylpiperazines as human melanocortin-4 receptor ligands
- Author
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Joe A. Tran, Nicole S. White, Jenny Wen, Joseph Pontillo, John Saunders, Caroline W. Chen, Dragan Marinkovic, Ajay Madan, Chen Chen, Alan C. Foster, Beth A. Fleck, Fabio C. Tucci, Wanlong Jiang, and Melissa Arellano
- Subjects
Clinical Biochemistry ,Pharmaceutical Science ,Pharmacology ,Ligands ,Blood–brain barrier ,Biochemistry ,Piperazines ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,medicine ,Animals ,Humans ,Potency ,Structure–activity relationship ,Receptor ,Piperazine ,Molecular Biology ,Molecular Structure ,Ligand ,Chemistry ,Organic Chemistry ,Amides ,In vitro ,Melanocortin 4 receptor ,medicine.anatomical_structure ,Receptor, Melanocortin, Type 4 ,Molecular Medicine - Abstract
A series of alpha-benzylpropionylpiperazines were synthesized and tested as antagonists of the melanocortin-4 receptor. In addition to its high potency and selectivity, R-11a had desirable pharmacokinetic properties including high brain penetration in mice.
- Published
- 2006
28. Distribution, metabolism, and excretion of the anti-angiogenic compound SU5416
- Author
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Andrew Parkinson, Juthamas Sukbuntherng, Christine Ye, Brian W. Ogilvie, Simon Wong, Weiwei Tan, David J. Sweeny, Lida Antonian, Qingling Zhang, and Ajay Madan
- Subjects
Indoles ,Cell ,Drug Evaluation, Preclinical ,Angiogenesis Inhibitors ,Biology ,Pharmacology ,Toxicology ,Receptor tyrosine kinase ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Species Specificity ,Pharmacokinetics ,medicine ,Animals ,Humans ,Distribution (pharmacology) ,Pyrroles ,Receptor ,Biotransformation ,Kinase ,Blood Proteins ,General Medicine ,Vascular endothelial growth factor ,medicine.anatomical_structure ,chemistry ,Injections, Intravenous ,biology.protein ,Autoradiography ,Tyrosine kinase ,Protein Binding - Abstract
SU5416, 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one, is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, Flk-1/KDR (fetal liver kinase 1/kinase insert domain-containing receptor), also known as VEGF receptor 2 (VEGFR2). It was the first VEGFR2 inhibitor to enter clinical trials for the treatment of colorectal and non-small cell lung cancers. Pre-clinical evaluation of SU5416 included studies related to the distribution, metabolism and excretion of this compound. These studies have provided information useful in understanding the disposition and metabolism of the indolinone class of chemicals, which has not been studied previously with therapeutic intent. The lessons we learned from SU5416 have been successfully applied in developing next generation indolinone compounds targeting tumor angiogenesis.
- Published
- 2006
29. Potent and orally active non-peptide antagonists of the human melanocortin-4 receptor based on a series of trans-2-disubstituted cyclohexylpiperazines
- Author
-
Dragan Marinkovic, Val S. Goodfellow, Stacy Markison, Jessica Parker, Alan C. Foster, Joseph Pontillo, L. Melissa Arellano, Beth A. Fleck, Nicole S. White, Margaret Joppa, Wanlong Jiang, Joe A. Tran, Caroline W. Chen, Kathleen Gogas, Fabio C. Tucci, Ajay Madan, Chen Chen, John Saunders, and Brian Dyck
- Subjects
medicine.medical_specialty ,Cachexia ,G protein ,Clinical Biochemistry ,Administration, Oral ,Biological Availability ,Pharmaceutical Science ,Biochemistry ,Piperazines ,Energy homeostasis ,Eating ,Structure-Activity Relationship ,Oral administration ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,G protein-coupled receptor ,Chemistry ,Organic Chemistry ,Antagonist ,Rats ,Bioavailability ,Melanocortin 4 receptor ,Endocrinology ,Receptor, Melanocortin, Type 4 ,Molecular Medicine ,Protein Binding - Abstract
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period.
- Published
- 2005
30. Effects of Prototypical Microsomal Enzyme Inducers on Cytochrome P450 Expression in Cultured Human Hepatocytes
- Author
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Patrick Koch, Karl Zech, L. Alayne Burton, Andrew Parkinson, Lida Antonian, Ajay Madan, Kathleen M. Carroll, Linda A. Krueger, Edward L. LeCluyse, Greg Wagner, Jameson Forster, Maciej Czerwinski, Liang-Shang Gan, April Downey, Richard A. Graham, Daniel R. Mudra, Maria D. Ribadeneira, Li Yu, and Philmore Robertson
- Subjects
CYP2B6 ,CYP3A ,Blotting, Western ,Pharmaceutical Science ,Enzyme-Linked Immunosorbent Assay ,Biology ,Pharmacology ,Mixed Function Oxygenases ,Cytochrome P-450 CYP2A6 ,Cytochrome P-450 CYP2C8 ,Cytochrome P-450 Enzyme System ,beta-Naphthoflavone ,Cytochrome P-450 CYP1A2 ,Isoniazid ,medicine ,Cytochrome P-450 CYP3A ,Humans ,Enzyme Inhibitors ,Enzyme inducer ,CYP2A6 ,Cells, Cultured ,CYP3A4 ,CYP1A2 ,Oxidoreductases, N-Demethylating ,CYP2E1 ,Cytochrome P-450 CYP2C19 ,Cytochrome P-450 CYP2B6 ,Liver ,Enzyme Induction ,Phenobarbital ,Hepatocytes ,biology.protein ,Aryl Hydrocarbon Hydroxylases ,Rifampin ,medicine.drug - Abstract
Cultured human hepatocytes are a valuable in vitro system for evaluating new molecular entities as inducers of cytochrome P450 (P450) enzymes. The present study summarizes data obtained from 62 preparations of cultured human hepatocytes that were treated with vehicles (saline or dimethylsulfoxide, 0.1%), beta-naphthoflavone (33 microM), phenobarbital (100 or 250 microM), isoniazid (100 microM) and/or rifampin (20 or 50 microM), and examined for the expression of P450 enzymes based on microsomal activity toward marker substrates, or in the case of CYP2C8, the level of immunoreactive protein. The results show that CYP1A2 activity was markedly induced by beta-naphthoflavone (on average 13-fold, n = 28 preparations), and weakly induced by phenobarbital (1.9-fold, n = 25) and rifampin (2.3-fold, n = 22); CYP2A6 activity tended to be increased with phenobarbital (n = 7) and rifampin (n = 3) treatments, but the effects were not statistically significant; CYP2B6 was induced by phenobarbital (6.5-fold, n = 13) and rifampin (13-fold, n = 14); CYP2C8 was induced by phenobarbital (4.0-fold, n = 4) and rifampin (5.2-fold, n = 4); CYP2C9 was induced by phenobarbital (1.8-fold, n = 14) and rifampin (3.5-fold, n = 10); CYP2C19 was markedly induced by rifampin (37-fold, n = 10), but relatively modestly by phenobarbital (7-fold, n = 9); CYP2D6 was not significantly induced by phenobarbital (n = 5) or rifampin (n = 5); CYP2E1 was induced by phenobarbital (1.7-fold, n = 5), rifampin (2.2-fold, n = 5), and isoniazid (2.3-fold, n = 5); and, CYP3A4 was induced by phenobarbital (3.3-fold, n = 42) and rifampin (10-fold, n = 61), but not by beta-naphthoflavone. Based on these observations, we generalize that beta-naphthoflavone induces CYP1A2 and isoniazid induces CYP2E1, whereas rifampin and, to a lesser extent phenobarbital, tend to significantly and consistently induce enzymes of the CYP2A, CYP2B, CYP2C, CYP2E, and CYP3A subfamilies but not the 2D subfamily.
- Published
- 2003
31. Identification of the Human P-450 Enzymes Responsible for the Sulfoxidation and Thiono-Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P-450 Enzymes in Disulfiram Bioactivation
- Author
-
Morris D. Faiman, Andrew Parkinson, and Ajay Madan
- Subjects
Medicine (miscellaneous) ,Aldehyde dehydrogenase ,Toxicology ,Isozyme ,Hydroxylation ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Culture Techniques ,Disulfiram ,medicine ,Humans ,Troleandomycin ,Enzyme Inhibitors ,Biotransformation ,chemistry.chemical_classification ,biology ,Cytochrome P450 ,Aldehyde Dehydrogenase ,CYP2E1 ,Psychiatry and Mental health ,Enzyme ,Biochemistry ,chemistry ,Microsomes, Liver ,biology.protein ,Microsome ,Ditiocarb ,Oxidation-Reduction ,Alcohol Deterrents ,medicine.drug - Abstract
Diethyldithiocarbamate methyl ester (DDTC-Me) is a precursorto the formation of S-methyl-N,N-diethylthiolcarbamate sulfoxide, the active metabolite proposed to be responsible for the alcohol deterrent effects of disulfiram. The present study investigated the role of human cytochrome P-450 (CYP) enzymes in sulfoxidation and thiono-oxidation of DDTC-Me, intermediary steps in the activation of disulfiram. Several approaches were used in an attempt to delineate the particular P-450 enzyme(s) involved in the sulfoxidation and thiono-oxidation of DDTC-Me. These approaches included the use of cDNA-expressed human P-450 enzymes, correlation analysis with sample-to-sample variation in human P-450 enzymes in a bank of human liver microsomes, and chemical and antibody inhibition studies. Multiple human P-450 enzymes (CYP3A4, CYP1A2, CYP2A6, and CYP2D6) catalyzed the sulfoxidation of DDTC-Me, as determined with cDNA-expressed enzymes. Several lines of evidence suggest that the sulfoxidation of DDTC-Me by human liver microsomes is primarily catalyzed by CYP3A4/5, including (1) a high correlation between DDTC-Me sulfoxidation and testosterone 6beta-hydroxylation; (2) increased DDTC-Me sulfoxidation in the presence of alpha-naphthoflavone, an activator of CYP3A enzymes; (3) inhibition of this reaction by inhibitors of CYP3A4/5 enzymes, such as troleandomycin and ketoconazole; and (4) inhibition of DDTC-Me sulfoxidation by antibodies against CYP3A enzymes. On the other hand, several lines of evidence suggested that the thiono-oxidation of DDTC-Me by human liver microsomes is catalyzed in part by CYP1A2, CYP2B6, CYP2E1, and CYP3A4/5, including (1) these human P450 enzymes among others have the capacity to catalyze this reaction, as determined with cDNA-expressed enzymes; (2) a high correlation between DDTC-Me thiono-oxidation and testosterone 6beta-hydroxylation, weak inhibition by ketoconazole, troleandomycin, and anti-CYP3A antibodies suggested a minor role for CYP3A4; (3) a high correlation with immunoreactive CYP2B6 suggested involvement of this enzyme; (4) weak inhibition of DDTC-Me thiono-oxidation by furafylline and anti-CYP1A antibody suggested involvement of CYP1A2; and (5) inhibition of DDTC-Me thiono-oxidation by DDTC and anti-CYP2E antibodies suggested a role for CYP2E1. Collectively, these data suggested CYP3A4/5 enzymes are the major contributors to the sulfoxidation of DDTC-Me by human liver microsomes, and CYP1A2, CYP2B6, CYP2E1, and CYP3A4/5 contribute toward DDTC-Me thiono-oxidation by human liver microsomes. This study, in conjunction with others (Madan et al., Drug Metab. Dispos. 23:1153-1162, 1995), may help explain the variability in disulfiram's effectiveness as an alcohol deterrent.
- Published
- 1998
32. Evaluation of Octamethylcyclotetrasiloxane (D4) as an Inducer of Rat Hepatic Microsomal Cytochrome P450, UDP-Glucuronosyltransferase, and Epoxide Hydrolase: A 28-Day Inhalation Study
- Author
-
Supratim Choudhuri, Gary B. Kolesar, Robert G. Meeks, Ajay Madan, James M. McKim, Richard W. Mast, Leland W. Dochterman, Paul C. wilga, John G. Breen, and Andrew Parkinson
- Subjects
Inhalation exposure ,medicine.medical_specialty ,biology ,Chemistry ,CYP1A2 ,Cytochrome P450 ,Toxicology ,Enzyme assay ,Epoxide hydrolase activity ,Endocrinology ,Biochemistry ,Internal medicine ,medicine ,biology.protein ,Microsome ,Enzyme inducer ,Epoxide hydrolase - Abstract
Repeated inhalation exposure to octamethylcyclotetrasiloxane (D4) produces a reversible and dose-related hepatomegaly and proliferation of hepatic endoplasmic reticulum in rats. However, the effects of D4 on the expression of cytochrome P450 enzymes have not been evaluated. In the present study, the time course for changes in hepatic microsomal cytochrome P450 enzyme expression following repeated inhalation exposure to D4 vapors was determined in male and female Fischer 344 rats. Animals were exposed to D4 vapor at concentrations of 70 and 700 ppm, via whole body inhalation for 6 h/day, 5 days/week for 4 weeks. Specified animals were euthanized on exposure days 3, 7, 14, 21, and 28. Microsomal fractions were prepared from fresh liver by differential centrifugation. Enzyme activity as well as immunoreactive protein levels of several cytochrome P450 enzymes (CYP), epoxide hydrolase, and UDP-glucuronosyltransferase (UDPGT) were evaluated. The time course for enzyme induction was monitored by measuring 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depentylase (PROD) activities on days 3, 7, 14, 21, and 28. CYP1A1/2 activity, as determined by EROD activity, was increased approximately 2- to 3-fold over the exposure period. However, an examination of immunoreactive protein revealed no induction of CYP1A1 and a suppression of CYP1A2 in the 700 ppm D4 group. In comparison, CYP2B1/2 enzyme activity, as determined by PROD, was significantly increased as early as day 3 in both the 70 and 700 ppm D4 groups of male and female rats. Overall, PROD activity on day 28 was induced more than 10-fold in the 70 ppm D4 groups and more than 20-fold in the 700 ppm D4 groups. The increase in PROD activity was paralleled by a comparable increase in CYP2B1/2 immunoreactive protein. There was a modest (2- to 3-fold) increase in CYP3A1/2 activity and immunoreactive protein, as determined by 6 beta-hydroxylation of testosterone and Western blot analysis. Expression of CYP enzymes was at or near maximum by day 14 and remained relatively constant throughout the exposure period. On day 28, epoxide hydrolase activity and immunoreactive protein were induced (2- to 3-fold) in a dose-dependent manner. Only slight changes in the expression and activity of UDPGT were detected, and these did not appear to be dose related. Thus, repeated inhalation exposure to D4 induces CYP enzymes and epoxide hydrolase in a manner similar to that observed for phenobarbital (PB). Therefore, D4 can be described as a "PB-like" inducer of hepatic microsomal enzymes in the Fischer 344 rat.
- Published
- 1998
33. Diagnosis of Castleman’s Disease by Identification of an Immunophenotypically Aberrant Population of Mantle Zone B Lymphocytes in Paraffin-Embedded Lymph Node Biopsies
- Author
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Shih Fen Chang, Markus Tiemann, Matthew S.T. Chow, John K. Camoriano, Reza Parwaresch, Thomas M. Habermann, Ajay Madan, and David M. Menke
- Subjects
Pathology ,medicine.medical_specialty ,Plasma cell ,Biology ,Immunophenotyping ,Immunoenzyme Techniques ,medicine ,Humans ,Lymph node ,Hyaline ,Retrospective Studies ,Gene Rearrangement ,B-Lymphocytes ,Paraffin Embedding ,Genes, Immunoglobulin ,Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor ,Castleman Disease ,Mantle zone ,Plasmacytosis ,Antibodies, Monoclonal ,Germinal center ,General Medicine ,Gene rearrangement ,Germinal Center ,medicine.disease ,Immunohistochemistry ,Lymphoma ,medicine.anatomical_structure ,POEMS Syndrome ,Lymph Nodes - Abstract
Castleman's disease (CD) is characterized by lymph node enlargement due to hyperplasia of abnormal lymphoid follicles and paracortical lymphocytic hyaline vascular (HV) stroma or plasmacytosis (PC). The lymphoid follicles in CD show involuted germinal centers and prominent mantle zone lymphocytes. Ninety-seven cases clinically suspected to be CD were analyzed according to conventional histologic criteria established by Castleman and Keller for diagnosis. Twenty-two cases were excluded as nonspecific hyperplasia (12); Hodgkin's and non-Hodgkin's lymphoma (9); and multiple myeloma involving lymph node paracortex (1). The 75 remaining cases, consisting of 51 cases of CD and 24 with altered follicles or paracortex suggestive of CD, were further analyzed immunohistologically for changes in follicular dendritic reticulum cells (FDRC) using the monoclonal antibody Ki-M4p, for germinal center proliferation with Ki-S5, for mantle zone immunophenotype with Ki-B3 and Ki-B5, for paracortical plasmacytoid monocytes with Ki-M1p, and for plasma cell clonality by applying antibodies to kappa and lambda immunoglobulin light chains. Lymph nodes showing nonspecific follicular and paracortical hyperplasia were included as controls. Hyaline vascular CD and plasma cell CD showed enlarged, polyploid FDRC with prominent nucleoli, decreased germinal center proliferation, and mantle zone populations of immunophenotypically aberrant, Ki-B3-negative B lymphocytes. Thirty-seven percent of hyaline vascular CD and plasma cell CD contained plasmacytoid monocytes, and 15% showed interstitial areas of lambda predominant plasma cells. Plasmacytoid monocytes were common in hyaline vascular CD but rare in plasma cell CD. Cases suspected to be CD that demonstrated a mantle zone population of Ki-B3-negative B lymphocytes had clinical finding of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal paraprotein, and skin changes or sclerotic bone lesions) syndrome and were reclassified as hyaline vascular CD, plasma cell CD, and mantle zone CD with an aberrant mantle zone immunophenotype only (lacking follicular center and paracortical histologic or immunohistologic abnormalities). Immunohistochemistry was valuable for identification of dysplastic FDRC, decreased germinal center proliferation, and plasmacytoid monocytes. In addition, immunohistochemistry was essential for detection of plasma cell clonality, an aberrant mantle zone immunophenotype, and mantle-zone-restricted CD that was devoid of diagnostic alterations of germinal center or paracortex.
- Published
- 1996
34. Lead optimization of 2-(piperidin-3-yl)-1H-benzimidazoles: identification of 2-morpholin- and 2-thiomorpholin-2-yl-1H-benzimidazoles as selective and CNS penetrating H₁-antihistamines for insomnia
- Author
-
Satheesh Babu, Ravula, Jinghua, Yu, Joe A, Tran, Melissa, Arellano, Fabio C, Tucci, Wilna J, Moree, Bin-Feng, Li, Robert E, Petroski, Jianyun, Wen, Siobhan, Malany, Samuel R J, Hoare, Ajay, Madan, Paul D, Crowe, and Graham, Beaton
- Subjects
Central Nervous System ,ERG1 Potassium Channel ,Nitrogen ,Morpholines ,Ether-A-Go-Go Potassium Channels ,Electrophysiology ,Inhibitory Concentration 50 ,Kinetics ,Structure-Activity Relationship ,Models, Chemical ,Piperidines ,Drug Design ,Sleep Initiation and Maintenance Disorders ,Histamine H1 Antagonists ,Microsomes, Liver ,Humans ,Hypnotics and Sedatives ,Benzimidazoles ,Receptors, Histamine H1 - Abstract
The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.
- Published
- 2011
35. Role of flavin-dependent monooxygenases and cytochrome P450 enzymes in the sulfoxidation of S-methyl N,N-diethylthiolcarbamate
- Author
-
Ajay Madan, Morris D. Faiman, and Andrew Parkinson
- Subjects
Male ,Metabolite ,Aldehyde dehydrogenase ,Flavin group ,Biochemistry ,Antibodies ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Thiocarbamates ,Disulfiram ,Animals ,Biotransformation ,Pharmacology ,chemistry.chemical_classification ,biology ,Cytochrome P450 ,Metabolism ,Monooxygenase ,Rats ,Enzyme ,chemistry ,Sulfoxides ,Microsomes, Liver ,Oxygenases ,biology.protein ,Microsome ,Ditiocarb - Abstract
Disulfiram is bioactivated to S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO), the metabolite proposed to be responsible for the action of disulfiram as an aldehyde dehydrogenase inhibitor. This bioactivation process includes a reduction, an S-methylation, and two successive oxidations. Sulfur-containing functional groups are substrates for cytochrome P450 enzymes or flavin-containing monooxygenases (FMO). In the present study, we investigated the contribution of these monooxygenases to the formation of DETC-MeSO from its immediate precursor S-methyl N,N-diethylthiolcarbamate (DETC-Me). Liver microsomes obtained from mature male rats were incubated with DETC-Me. The formation of DETC-MeSO was blocked completely by solubilization of the microsomes with the detergent Emulgen 911, or by the presence of the cytochrome P450 inhibitor 1-benzylimidazole. However, thermal-inactivation of FMO resulted in only a partial loss in DETC-MeSO formation. Liver microsomes from phenobarbital-treated rats showed a 4- to 5-fold increase in the rate of formation of DETC-MeSO, compared with controls. Liver microsomes from pyrazole-treated rats showed a 50% decrease in the sulfoxidation of DETC-Me compared with controls. In a purified reconstituted system, cytochrome P450 2B1 (CYP2B1) catalyzed the formation of DETC-MeSO at a rate of 51 nmol DETC-MeSO formed/min/nmol cytochrome P450. Antibodies to CYP2B1 caused a 60% inhibition of DETC-MeSO formation by liver microsomes from phenobarbital-treated rats. These results suggest that in male rat liver microsomes, cytochrome P450 plays a major role in catalyzing the sulfoxidation of DETC-Me, whereas FMO plays a minor role (< 10%). Also, in liver microsomes from phenobarbital-treated rats, CYP2B1 is the major catalyst for the sulfoxidation of DETC-Me.
- Published
- 1993
36. Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia
- Author
-
Sam R. J. Hoare, Graham Beaton, Bin-Feng Li, Paul D. Crowe, Said Zamani-Kord, Lisa M. Hernández, Wilna J. Moree, Charles Q. Huang, Jinghua Yu, Hua Wang, Siobhan Malany, Fabio C. Tucci, Chun Yang, Ajay Madan, Aida Sacaan, Robert E. Petroski, Jianyun Wen, Coon Timothy Richard, Margaret J. Bradbury, Kayvon Jalali, and Dragan Marinkovic
- Subjects
CYP2D6 ,Clinical Biochemistry ,hERG ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Structure-Activity Relationship ,MicroDose ,Pharmacokinetics ,In vivo ,Sleep Initiation and Maintenance Disorders ,Drug Discovery ,Structure–activity relationship ,Animals ,Dimethindene ,Humans ,Receptors, Histamine H1 ,Molecular Biology ,Unspecific monooxygenase ,biology ,Chemistry ,Organic Chemistry ,Antagonist ,Electroencephalography ,Rats ,Pyridazines ,Cytochrome P-450 CYP2D6 ,Indenes ,Models, Animal ,biology.protein ,Histamine H1 Antagonists ,Microsomes, Liver ,Molecular Medicine - Abstract
Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.
- Published
- 2010
37. Selectivity profiling of novel indene H(1)-antihistamines for the treatment of insomnia
- Author
-
Paul D. Crowe, Chun Yang, Robert E. Petroski, Kayvon Jalali, Coon Timothy Richard, Wilna J. Moree, Sam R. J. Hoare, Bin-Feng Li, Said Zamani-Kord, Hua Wang, Graham Beaton, Siobhan Malany, Jianyun Wen, Ajay Madan, and Jinghua Yu
- Subjects
biology ,Chemistry ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,hERG ,Histamine Antagonists ,Pharmaceutical Science ,M1 muscarinic receptor ,Biochemistry ,chemistry.chemical_compound ,Indenes ,In vivo ,Sleep Initiation and Maintenance Disorders ,Drug Discovery ,biology.protein ,Molecular Medicine ,Humans ,Cyp enzymes ,Indene ,Selectivity ,Molecular Biology ,ADME - Abstract
A series of indene analogs of the H1-antihistamine (−)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led to the identification of several potent H1-antihistamines with desirable selectivity over CYP enzymes, the M1 muscarinic receptor and the hERG channel. These compounds were candidates for further ADME profiling and in vivo evaluation.
- Published
- 2010
38. Novel benzothiophene H1-antihistamines for the treatment of insomnia
- Author
-
Coon Timothy Richard, Raymond S. Gross, Siobhan Malany, Florence Jovic, Wilna J. Moree, Zhihong O’Brien, Sam R. J. Hoare, Paul D. Crowe, Fabio C. Tucci, Bin-Feng Li, Graham Beaton, Margaret J. Bradbury, Hua Wang, Jianyun Wen, Robert E. Petroski, Jinghua Yu, Aida Sacaan, Dragan Marinkovic, Lisa M. Hernández, and Ajay Madan
- Subjects
Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Benzothiophene ,Histamine H1 receptor ,Thiophenes ,Pharmacology ,Biochemistry ,chemistry.chemical_compound ,Structure-Activity Relationship ,MicroDose ,Pharmacokinetics ,Sleep Initiation and Maintenance Disorders ,Drug Discovery ,Histamine H1 Antagonists ,Molecular Medicine ,Humans ,Receptors, Histamine H1 ,Molecular Biology - Abstract
SAR of lead benzothiophene H1-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H1-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.
- Published
- 2009
39. Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia
- Author
-
Fabio C. Tucci, Lisa M. Hernández, Graham Beaton, Ajay Madan, Bin-Feng Li, Margaret J. Bradbury, Robert E. Petroski, Wilna J. Moree, Hua Wang, Dragan Marinkovic, Jinghua Yu, Jianyun Wen, Raymond S. Gross, Siobhan Malany, Florence Jovic, Paul D. Crowe, Said Zamani-Kord, Coon Timothy Richard, Zhihong O’Brien, Aida Sacaan, and Sam R. J. Hoare
- Subjects
Tertiary amine ,hERG ,Pharmacology ,Substrate Specificity ,chemistry.chemical_compound ,Pharmacokinetics ,In vivo ,Sleep Initiation and Maintenance Disorders ,Drug Discovery ,medicine ,Animals ,Dimethindene ,Humans ,Dosing ,Sleep disorder ,biology ,Chemistry ,Antagonist ,Benzothiophene ,Brain ,Electroencephalography ,medicine.disease ,Receptors, Muscarinic ,Ether-A-Go-Go Potassium Channels ,Rats ,Biochemistry ,biology.protein ,Histamine H1 Antagonists ,Molecular Medicine ,Sleep - Abstract
Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.
- Published
- 2009
40. Validation and application of a liquid chromatography-tandem mass spectrometric method for the simultaneous determination of testosterone and dihydrotestosterone in rat prostatic tissue using a 96-well format
- Author
-
Michael S. Brown, Noah Post, Coon Timothy Richard, Trudy A. Kohout, Rosa Luo, Zhihong O’Brien, and Ajay Madan
- Subjects
Male ,endocrine system ,Calibration curve ,medicine.drug_class ,Clinical Biochemistry ,In Vitro Techniques ,urologic and male genital diseases ,Biochemistry ,High-performance liquid chromatography ,Analytical Chemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Microtiter plate ,Liquid chromatography–mass spectrometry ,Tandem Mass Spectrometry ,medicine ,Animals ,Testosterone ,Derivatization ,Detection limit ,Chromatography ,Prostate ,Reproducibility of Results ,Dihydrotestosterone ,Cell Biology ,General Medicine ,Androgen ,Rats ,chemistry ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug ,Chromatography, Liquid - Abstract
A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to extract and quantify the androgen concentration in the rat prostate. This method introduced a novel 96-well plate format for the extraction and derivatization of testosterone (T) and dihydrotestosterone (DHT) from rat prostatic tissue that greatly simplified the sample preparation procedure. Due to the difficulty to obtain reproducible specimens with non-detectable level of androgen, a matrix-free standard solution was used for method validation. Both T and DHT calibration curves were linear over the calibration range (12.5-2500 pg) with correlation coefficient values greater than 0.9900. The intra-day and inter-day accuracy, reported as %bias, and precision, reported as %CV, of T and DHT were within +/-10%. The lower limit of detection (LLOD) and lower limits of quantification (LLOQ) for both T and DHT were determined to be 5 and 12.5 pg. The validation results demonstrated the selectivity, sensitivity, accuracy, precision, linearity and ruggedness of the method, as well as the suitability of the method for simultaneous detection of T and DHT in rat prostatic tissues. The validated method was successfully applied to determine the physiological T and DHT level in rat prostatic tissues. Similarly to the serum concentration profile pattern, T and DHT intraprostatic levels peaked 2 h after lights-on and decreased after lights-off with DHT level approximately 4-fold greater than T.
- Published
- 2009
41. N-[6-amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A2A receptor antagonists with improved drug like properties and in vivo efficacy
- Author
-
Raymond S. Gross, John P. Williams, Tanya Joswig, Emily Lin, Stacy Markison, Deborah H. Slee, Marion Lanier, William Kargo, Jaime Piercey, Jose-Luis Diaz, Zhiyong Luo, John E. Tellew, Zhihong O’Brien, Marilyn Zhao, Siobhan Malany, Kayvon Jalali, Mark Santos, Sandra M. Lechner, Ajay Madan, Xiaohu Zhang, Jenny Wen, Yongsheng Chen, Manisha Moorjani, Robert E. Petroski, María I. Crespo, and John Saunders
- Subjects
Rotation ,Stereochemistry ,Substituent ,Adenosine A1 Receptor Antagonists ,Chemical synthesis ,Turn (biochemistry) ,chemistry.chemical_compound ,Structure-Activity Relationship ,Amide ,Drug Discovery ,Acetamides ,Animals ,Humans ,Solubility ,Alkyl ,chemistry.chemical_classification ,Catalepsy ,Behavior, Animal ,Chemistry ,Aromaticity ,Drug Synergism ,Small molecule ,Adenosine A2 Receptor Antagonists ,Rats ,Pyrimidines ,Molecular Medicine ,Haloperidol - Abstract
In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA2A) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R1 is an aromatic heterocycle, R2 is a short-chain alkyl amide, and the typical R3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.
- Published
- 2009
42. Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor
- Author
-
Charles Q. Huang, Martin W. Rowbottom, Joseph Pontillo, Yun-Fei Zhu, Zhiqiang Guo, Warren Wade, Ajay Madan, Greg J. Reinhart, Qiu Xie, Chen Chen, Dongpei Wu, Haig Bozigian, John Saunders, Fabio C. Tucci, Mi Chen, R. Scott Struthers, Takung Chen, Jenny Wen, and Yongsheng Chen
- Subjects
Male ,Time Factors ,Hydrocarbons, Fluorinated ,Stereochemistry ,Carboxylic acid ,Drug Evaluation, Preclinical ,Butyrate ,Butyric acid ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Animals ,Humans ,chemistry.chemical_classification ,Trifluoromethyl ,Molecular Structure ,Antagonist ,Uracil ,Stereoisomerism ,Macaca fascicularis ,Pyrimidines ,chemistry ,Hormone receptor ,Microsomes, Liver ,Molecular Medicine ,Cytochrome P-450 CYP3A Inhibitors ,Caco-2 Cells ,Gonadotropin-releasing hormone receptor ,Receptors, LHRH - Abstract
The discovery of novel uracil phenylethylamines bearing a butyric acid as potent human gonadotropin-releasing hormone receptor (hGnRH-R) antagonists is described. A major focus of this optimization was to improve the CYP3A4 inhibition liability of these uracils while maintaining their GnRH-R potency. R-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyric acid sodium salt, 10b (elagolix), was identified as a potent and selective hGnRH-R antagonist. Oral administration of 10b suppressed luteinizing hormone in castrated macaques. These efforts led to the identification of 10b as a clinical compound for the treatment of endometriosis.
- Published
- 2008
43. Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain
- Author
-
Mingzhu Zhang, Florence Jovic, Michael Johns, Troy Vickers, Joe A. Tran, Bin-Feng Li, Julie O'Brien, Margaret J. Bradbury, Jenny Wen, Rebecca R. Pick, John Saunders, Beth A. Fleck, Brian Dyck, Junko Tamiya, Alan C. Foster, Ajay Madan, Chen Chen, and Jonathan Grey
- Subjects
Cyclopropanes ,Male ,Models, Molecular ,Analgesic ,Administration, Oral ,Biological Availability ,Pharmacology ,Crystallography, X-Ray ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Structure-Activity Relationship ,Milnacipran ,Drug Discovery ,medicine ,Animals ,Humans ,Neurotransmitter ,Serotonin transporter ,Pain Measurement ,Serotonin Plasma Membrane Transport Proteins ,Norepinephrine Plasma Membrane Transport Proteins ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Stereoisomerism ,Rats ,Molecular Weight ,Disease Models, Animal ,Spinal Nerves ,Biochemistry ,chemistry ,Drug Design ,Neuropathic pain ,Lipophilicity ,biology.protein ,Microsomes, Liver ,Molecular Medicine ,Neuralgia ,Serotonin ,Caco-2 Cells ,Reuptake inhibitor ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
- Published
- 2008
44. In vitro metabolism of indiplon and an assessment of its drug interaction potential
- Author
-
L Jin, Ajay Madan, Andrew Fisher, Haig Bozigian, and D Chapman
- Subjects
Furafylline ,Health, Toxicology and Mutagenesis ,Thiophenes ,Pharmacology ,Toxicology ,Biochemistry ,chemistry.chemical_compound ,Carboxylesterase ,Benzodiazepines ,medicine ,Cytochrome P-450 Enzyme Inhibitors ,Humans ,Hypnotics and Sedatives ,Drug Interactions ,Troleandomycin ,CYP3A4 ,biology ,CYP1A2 ,Cytochrome P450 ,General Medicine ,chemistry ,Indiplon ,Microsome ,biology.protein ,Microsomes, Liver ,Carboxylic Ester Hydrolases ,medicine.drug - Abstract
This study was designed to study the in vitro metabolism of indiplon, a novel hypnotic agent, and to assess its potential to cause drug interactions. In incubations with pooled human liver microsomes, indiplon was converted to two major, pharmacologically inactive metabolites, N-desmethyl-indiplon and N-desacetyl-indiplon. The N-deacetylation reaction did not require NADPH, and appeared to be catalyzed by organophosphate-sensitive microsomal carboxylesterases. The N-demethylation of indiplon was catalyzed by CYP3A4/5 based on the following observations: (1) the sample-to-sample variation in N-demethylation of indiplon ([S] = 100 microM) in a bank of human liver microsomes was strongly correlated with testosterone 6beta-hydroxylase (CYP3A4/5) activity (r(2) = 0.98), but not with any other CYP enzyme; (2) recombinant CYP1A1, CYP1A2, CYP3A4, CYP3A5 and CYP3A7 had the ability to catalyze this reaction; (3) the N-demethylation of indiplon was inhibited by CYP3A4/5 inhibitors (ketoconazole and troleandomycin), but not by a CYP1A2 inhibitor (furafylline). In pooled human liver microsomes, indiplon exhibited a weak capacity to inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5 and carboxylesterase (p-nitrophenylacetate hydrolysis) activities (IC50 >/= 20 microM). Clinical data available on indiplon support the conclusions of this paper that the in vitro metabolism of indiplon is catalyzed by multiple enzymes, and indiplon is a weak inhibitor of human CYP enzymes.
- Published
- 2007
45. Pyrrolidinones as orally bioavailable antagonists of the human melanocortin-4 receptor with anti-cachectic activity
- Author
-
John Saunders, Joe A. Tran, Stacy Markison, Nicole S. White, Beth A. Fleck, Sam R. J. Hoare, Daniel L. Marks, Melissa Arellano, Joseph Pontillo, Ajay Madan, Chen Chen, Dragan Marinkovic, Alan C. Foster, Wanlong Jiang, Caroline W. Chen, Fabio C. Tucci, and Jenny Wen
- Subjects
Male ,Cachexia ,Clinical Biochemistry ,Pharmaceutical Science ,Administration, Oral ,Biological Availability ,Pharmacology ,Biochemistry ,Mice ,Structure-Activity Relationship ,In vivo ,Oral administration ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Humans ,Pyrrolidinones ,Receptor ,Molecular Biology ,Molecular Structure ,Chemistry ,digestive, oral, and skin physiology ,Organic Chemistry ,Body Weight ,Antagonist ,medicine.disease ,Melanocortin 4 receptor ,Mice, Inbred C57BL ,Disease Models, Animal ,Body Composition ,Molecular Medicine ,Receptor, Melanocortin, Type 4 ,hormones, hormone substitutes, and hormone antagonists - Abstract
A series of pyrrolidinones derived from phenylalanines were synthesized as potent antagonists of the human melanocortin-4 receptor. These compounds showed high potencies and selectivities, and several of them had good oral bioavailabilities. In addition, 12e demonstrated in vivo efficacy in a murine cachexia model.
- Published
- 2006
46. A thienopyridazinone-based melanin-concentrating hormone receptor 1 antagonist with potent in vivo anorectic properties
- Author
-
John Saunders, David A. Schwarz, Martin W. Rowbottom, Liren Zhao, Mingzhu Zhang, Val S. Goodfellow, Christopher E. Heise, Troy Vickers, Stacy Markison, Junko Tamiya, Katie Sorensen, Christi Norton, Brian Dyck, Jonathan Grey, Ajay Madan, Paul J. Conlon, and Jenny Wen
- Subjects
Male ,Melanin-concentrating hormone ,Biological Availability ,Thiophenes ,Pharmacology ,Permeability ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Eating ,Structure-Activity Relationship ,In vivo ,Oral administration ,Drug Discovery ,Appetite Depressants ,Animals ,Obesity ,Receptors, Somatostatin ,Receptor ,Body Weight ,Antagonist ,Brain ,Stereoisomerism ,In vitro ,Melanin-concentrating hormone receptor ,Rats ,Pyridazines ,chemistry ,Biochemistry ,Anorectic ,Molecular Medicine ,Half-Life - Abstract
Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailabilty in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg-1.
- Published
- 2006
47. Synthesis and structure-activity relationships of retro bis-aminopyrrolidine urea (rAPU) derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1). Part 2
- Author
-
David A. Schwarz, William Ban, Wesley J. Dwight, Jenny Wen, Joseph Pontillo, Martin W. Rowbottom, Val S. Goodfellow, Dongpei Wu, Christopher E. Heise, Sarah Hudson, Troy Vickers, Brett Ching, Warren Wade, Ajay Madan, Hua Wang, and Mehrak Kiankarimi
- Subjects
Pyrrolidines ,Melanin-concentrating hormone ,medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Carboxamide ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Urea ,Receptors, Somatostatin ,skin and connective tissue diseases ,Receptor ,Molecular Biology ,biology ,Molecular Structure ,Organic Chemistry ,Small molecule ,Melanin-concentrating hormone receptor ,Rats ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.
- Published
- 2006
48. Substituted chromones and quinolones as potent melanin-concentrating hormone receptor 1 antagonists
- Author
-
Junko Tamiya, Liren Zhao, Joseph Pontillo, Warren Wade, Ajay Madan, David A. Schwarz, Christi Norton, Jenny Wen, Sarah Hudson, Brett Ching, Brian Dyck, Christopher E. Heise, and Val S. Goodfellow
- Subjects
Time Factors ,Melanin-concentrating hormone ,Chemistry, Pharmaceutical ,Clinical Biochemistry ,Pharmaceutical Science ,Administration, Oral ,Quinolones ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Animals ,Humans ,Receptors, Pituitary Hormone ,Molecular Biology ,G protein-coupled receptor ,Melanins ,Chemistry ,Organic Chemistry ,In vitro ,Melanin-concentrating hormone receptor ,Bioavailability ,Rats ,Models, Chemical ,Hormone receptor ,Chromones ,Drug Design ,Microsomes, Liver ,Molecular Medicine - Abstract
A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.
- Published
- 2006
49. Synthesis and structure-activity relationships of retro bis-aminopyrrolidine urea (rAPU) derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1). Part 1
- Author
-
David A. Schwarz, Brian Dyck, Warren Wade, Christopher E. Heise, Mehrak Kiankarimi, Andrew Fisher, Ajay Madan, Troy Vickers, Val S. Goodfellow, Jonathan Grey, Martin W. Rowbottom, Mingzhu Zhang, Wesley J. Dwight, Robert E. Petroski, Dongpei Wu, and Junko Tamiya
- Subjects
endocrine system ,Pyrrolidines ,Melanin-concentrating hormone ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Structure-Activity Relationship ,Drug Discovery ,Structure–activity relationship ,Animals ,Urea ,Receptors, Pituitary Hormone ,Molecular Biology ,Molecular Structure ,Organic Chemistry ,Small molecule ,In vitro ,Bioavailability ,Melanin-concentrating hormone receptor ,Rats ,chemistry ,Molecular Medicine - Abstract
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited potent binding affinity and functional activity at MCH-R1, and good oral bioavailability in rat.
- Published
- 2006
50. Regulation of drug transporter gene expression by nuclear receptors
- Author
-
Jeff L. Staudinger, Andrew Parkinson, Kathleen M. Carol, and Ajay Madan
- Subjects
medicine.medical_specialty ,Receptors, Steroid ,Organic Cation Transport Proteins ,CYP3A ,Pharmaceutical Science ,Receptors, Cytoplasmic and Nuclear ,digestive system ,Polymerase Chain Reaction ,chemistry.chemical_compound ,Mice ,Internal medicine ,Gene expression ,Constitutive androstane receptor ,medicine ,Animals ,Cytochrome P-450 CYP3A ,Testosterone ,Constitutive Androstane Receptor ,Pharmacology ,Pregnane X receptor ,biology ,Pregnane X Receptor ,Cytochrome P450 ,Biological Transport ,Oxidoreductases, N-Demethylating ,Organ Size ,Receptor Cross-Talk ,Blotting, Northern ,digestive system diseases ,Endocrinology ,Nuclear receptor ,chemistry ,Gene Expression Regulation ,ABCC3 ,Phenobarbital ,biology.protein ,Microsomes, Liver ,Androstane ,Aryl Hydrocarbon Hydroxylases ,Multidrug Resistance-Associated Proteins ,Hepatomegaly ,Transcription Factors - Abstract
Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are key regulators of xenobiotic-inducible cytochrome P450 gene expression. Whereas much is known about their role in regulating drug metabolism, little is known regarding their role in regulating drug transport in vivo. Wild-type mice and mice lacking PXR (PXR-KO) were used to examine the inducible expression of two drug transporter genes, Oatp2 (Slc21a5) and Mrp3 (Abcc3), in liver following treatment with selective PXR and CAR activators. Selective activation of PXR or CAR induced Oatp2 and Mrp3 expression in wild-type mice but not in PXR-KO mice. Basal expression levels of Oatp2 and Mrp3 gene were significantly higher in PXR-KO mice when compared with wild-type mice. Additionally, phenobarbital (PB)-inducible Oatp2 and Mrp3 gene expression was significantly increased in the PXR-KO mice when compared with wild-type PB-treated mice. We also examined the effect of PXR ablation on PB-inducible hepatic CYP3A activity in vivo. Microsomes isolated from PB-treated PXR-KO mice exhibited a significantly elevated rate of testosterone 6 beta-hydroxylation when compared with microsomes isolated from wild-type PB-treated mice. PB treatment produced significantly increased levels of hepatomegaly in PXR-KO mice when compared with wild-type PB-treated mice. Taken together, these results suggest that nonliganded PXR plays a net negative role in coregulating shared PXR/CAR-target gene expression in vivo and extend the hypothesis that PXR and CAR coregulate not only drug metabolism but also drug transport.
- Published
- 2003
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