56 results on '"Bilodeau MT"'
Search Results
2. Novel Miniaturized Drug Conjugate Leverages HSP90-driven Tumor Accumulation to Overcome PI3K Inhibitor Delivery Challenges to Solid Tumors.
- Author
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Perino S, Moreau B, Freda J, Cirello A, White BH, Quinn JM, Kriksciukaite K, Someshwar A, Romagnoli J, Robinson M, Movassaghian S, Cipriani T, Wooster R, Bilodeau MT, and Whalen KA
- Subjects
- Animals, Apoptosis, Cell Proliferation, Female, HSP90 Heat-Shock Proteins chemistry, Humans, Mice, Mice, Nude, Neoplasms metabolism, Neoplasms pathology, Phosphatidylinositol 3-Kinases metabolism, Protein Kinase Inhibitors chemistry, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Drug Delivery Systems, HSP90 Heat-Shock Proteins metabolism, Neoplasms drug therapy, Phosphatidylinositol 3-Kinases chemistry, Protein Kinase Inhibitors pharmacology
- Abstract
The PI3K pathway is considered a master regulator for cancer due to its frequent activation, making it an attractive target for pharmacologic intervention. While substantial efforts have been made to develop drugs targeting PI3K signaling, few drugs have been able to achieve the inhibition necessary for effective tumor control at tolerated doses. HSP90 is a chaperone protein that is overexpressed and activated in many tumors and as a consequence, small-molecule ligands of HSP90 are preferentially retained in tumors up to 20 times longer than in normal tissue. We hypothesize that the generation of conjugates that use a HSP90-targeting ligand and a payload such as copanlisib, may open the narrow therapeutic window of this and other PI3K inhibitors. In support of this hypothesis, we have generated a HSP90-PI3K drug conjugate, T-2143 and utilizing xenograft models, demonstrate rapid and sustained tumor accumulation of the conjugate, deep pathway inhibition, and superior efficacy than the PI3K inhibitor on its own. Selective delivery of T-2143 and the masking of the inhibitor active site was also able to mitigate a potentially dose-limiting side effect of copanlisib, hyperglycemia. These data demonstrate that by leveraging the preferential accumulation of HSP90-targeting ligands in tumors, we can selectively deliver a PI3K inhibitor leading to efficacy in multiple tumor models without hyperglycemia in mice. These data highlight a novel drug delivery strategy that allows for the potential opening of a narrow therapeutic window through specific tumor delivery of anticancer payloads and reduction of toxicity., (©2020 American Association for Cancer Research.)
- Published
- 2020
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3. Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer.
- Author
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Whalen KA, White BH, Quinn JM, Kriksciukaite K, Alargova R, Au Yeung TP, Bazinet P, Brockman A, DuPont MM, Oller H, Gifford J, Lemelin CA, Lim Soo P, Perino S, Moreau B, Sharma G, Shinde R, Sweryda-Krawiec B, Bilodeau MT, and Wooster R
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Immunoconjugates chemistry, Immunoconjugates pharmacology, Lung Neoplasms metabolism, Mice, Miniaturization, Small Cell Lung Carcinoma metabolism, Up-Regulation, Xenograft Model Antitumor Assays, Immunoconjugates administration & dosage, Lung Neoplasms drug therapy, Maytansine chemistry, Receptors, Somatostatin antagonists & inhibitors, Small Cell Lung Carcinoma drug therapy
- Abstract
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a 95% mortality rate with no improvement to treatment in decades, and new therapies are desperately needed. PEN-221 is a miniaturized peptide-drug conjugate (∼2 kDa) designed to target SCLC via a Somatostatin Receptor 2 (SSTR2)-targeting ligand and to overcome the high proliferation rate characteristic of this disease by using the potent cytotoxic payload, DM1. SSTR2 is an ideal target for a drug conjugate, as it is overexpressed in SCLC with limited normal tissue expression. In vitro , PEN-221 treatment of SSTR2-positive cells resulted in PEN-221 internalization and receptor-dependent inhibition of cellular proliferation. In vivo , PEN-221 exhibited rapid accumulation in SSTR2-positive SCLC xenograft tumors with quick clearance from plasma. Tumor accumulation was sustained, resulting in durable pharmacodynamic changes throughout the tumor, as evidenced by increases in the mitotic marker of G
2 -M arrest, phosphohistone H3, and increases in the apoptotic marker, cleaved caspase-3. PEN-221 treatment resulted in significant antitumor activity, including complete regressions in SSTR2-positive SCLC xenograft mouse models. Treatment was effective using a variety of dosing schedules and at doses below the MTD, suggesting flexibility of dosing schedule and potential for a large therapeutic window in the clinic. The unique attributes of the miniaturized drug conjugate allowed for deep tumor penetration and limited plasma exposure that may enable long-term dosing, resulting in durable tumor control. Collectively, these data suggest potential for antitumor activity of PEN-221 in patients with SSTR2-positive SCLC., (©2019 American Association for Cancer Research.)- Published
- 2019
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4. Discovery of an SSTR2-Targeting Maytansinoid Conjugate (PEN-221) with Potent Activity in Vitro and in Vivo.
- Author
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White BH, Whalen K, Kriksciukaite K, Alargova R, Au Yeung T, Bazinet P, Brockman A, DuPont M, Oller H, Lemelin CA, Lim Soo P, Moreau B, Perino S, Quinn JM, Sharma G, Shinde R, Sweryda-Krawiec B, Wooster R, and Bilodeau MT
- Subjects
- Animals, Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic pharmacokinetics, Antineoplastic Agents, Phytogenic pharmacology, CHO Cells, Cell Line, Cricetulus, Dogs, Humans, Immunoconjugates chemistry, Immunoconjugates pharmacology, Maytansine chemistry, Maytansine pharmacokinetics, Mice, Receptors, Somatostatin metabolism, Xenograft Model Antitumor Assays, Drug Discovery, Maytansine pharmacology, Receptors, Somatostatin drug effects
- Abstract
Somatostatin receptor 2 (SSTR2) is frequently overexpressed on several types of solid tumors, including neuroendocrine tumors and small-cell lung cancer. Peptide agonists of SSTR2 are rapidly internalized upon binding to the receptor and linking a toxic payload to an SSTR2 agonist is a potential method to kill SSTR2-expressing tumor cells. Herein, we describe our efforts towards an efficacious SSTR2-targeting cytotoxic conjugate; examination of different SSTR2-targeting ligands, conjugation sites, and payloads led to the discovery of 22 (PEN-221), a conjugate consisting of microtubule-targeting agent DM1 linked to the C-terminal side chain of Tyr
3 -octreotate. PEN-221 demonstrates in vitro activity which is both potent (IC50 = 10 nM) and receptor-dependent (IC50 shifts 90-fold upon receptor blockade). PEN-221 targets high levels of DM1 to SSTR2-expressing xenograft tumors, which has led to tumor regressions in several SSTR2-expressing xenograft mouse models. The safety and efficacy of PEN-221 is currently under evaluation in human clinical trials.- Published
- 2019
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5. MK-7622: A First-in-Class M 1 Positive Allosteric Modulator Development Candidate.
- Author
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Beshore DC, N Di Marco C, Chang RK, Greshock TJ, Ma L, Wittmann M, Seager MA, Koeplinger KA, Thompson CD, Fuerst J, Hartman GD, Bilodeau MT, Ray WJ, and Kuduk SD
- Abstract
Identification of ligands that selectively activate the M
1 muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading to the clinical candidate MK-7622, a highly selective positive allosteric modulator of the M1 muscarinic receptor that has entered Phase II studies in patients with Alzheimer's disease., Competing Interests: The authors declare the following competing financial interest(s): Authors are current or former employees of Merck & Co., Inc., Kenilworth, NJ, U.S., and potentially own stock and/or hold stock options in the Company.- Published
- 2018
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6. Discovery of a 3-(4-Pyrimidinyl) Indazole (MLi-2), an Orally Available and Selective Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitor that Reduces Brain Kinase Activity.
- Author
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Scott JD, DeMong DE, Greshock TJ, Basu K, Dai X, Harris J, Hruza A, Li SW, Lin SI, Liu H, Macala MK, Hu Z, Mei H, Zhang H, Walsh P, Poirier M, Shi ZC, Xiao L, Agnihotri G, Baptista MA, Columbus J, Fell MJ, Hyde LA, Kuvelkar R, Lin Y, Mirescu C, Morrow JA, Yin Z, Zhang X, Zhou X, Chang RK, Embrey MW, Sanders JM, Tiscia HE, Drolet RE, Kern JT, Sur SM, Renger JJ, Bilodeau MT, Kennedy ME, Parker EM, Stamford AW, Nargund R, McCauley JA, and Miller MW
- Subjects
- Animals, Brain metabolism, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacokinetics, Humans, Indazoles administration & dosage, Indazoles pharmacokinetics, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 metabolism, Male, Molecular Docking Simulation, Parkinson Disease drug therapy, Parkinson Disease enzymology, Rats, Rats, Wistar, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Indazoles chemistry, Indazoles pharmacology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 antagonists & inhibitors
- Abstract
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
- Published
- 2017
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7. Discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity and pharmacokinetics.
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Wolkenberg SE, Nolt MB, Bilodeau MT, Trotter BW, Manley PJ, Kett NR, Nanda KK, Wu Z, Cato MJ, Kane SA, Kiss L, Spencer RH, Wang J, Lynch JJ, Regan CP, Stump GL, Li B, White R, Yeh S, Dinsmore CJ, Lindsley CW, and Hartman GD
- Subjects
- Drug Discovery, Humans, Pyridines pharmacokinetics, Structure-Activity Relationship, Kv1.5 Potassium Channel antagonists & inhibitors, Pyridines pharmacology
- Abstract
Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, I
Kur , has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current IKs , whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for IKur over IKs (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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8. Structural characterization of nonactive site, TrkA-selective kinase inhibitors.
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Su HP, Rickert K, Burlein C, Narayan K, Bukhtiyarova M, Hurzy DM, Stump CA, Zhang X, Reid J, Krasowska-Zoladek A, Tummala S, Shipman JM, Kornienko M, Lemaire PA, Krosky D, Heller A, Achab A, Chamberlin C, Saradjian P, Sauvagnat B, Yang X, Ziebell MR, Nickbarg E, Sanders JM, Bilodeau MT, Carroll SS, Lumb KJ, Soisson SM, Henze DA, and Cooke AJ
- Subjects
- Amino Acid Sequence, Binding Sites, Crystallography, X-Ray, Drug Evaluation, Preclinical, Humans, Kinetics, Membrane Glycoproteins antagonists & inhibitors, Membrane Glycoproteins chemistry, Membrane Glycoproteins genetics, Models, Molecular, Protein Conformation, Protein Kinase Inhibitors chemical synthesis, Receptor, trkA genetics, Receptor, trkB antagonists & inhibitors, Receptor, trkB chemistry, Receptor, trkB genetics, Receptor, trkC antagonists & inhibitors, Receptor, trkC chemistry, Receptor, trkC genetics, Recombinant Proteins chemistry, Recombinant Proteins drug effects, Recombinant Proteins genetics, Structure-Activity Relationship, Surface Plasmon Resonance, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Receptor, trkA antagonists & inhibitors, Receptor, trkA chemistry
- Abstract
Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases. The X-ray structures reveal a binding site outside the kinase active site that uses residues from the kinase domain and the juxtamembrane region. Three modes of binding with the juxtamembrane region are characterized through a series of ligand-bound complexes. The structures indicate a critical pharmacophore on the compounds that leads to the distinct binding modes. The mode of interaction can allow TrkA selectivity over TrkB and TrkC or promiscuous, pan-Trk inhibition. This finding highlights the difficulty in characterizing the structure-activity relationship of a chemical series in the absence of structural information because of substantial differences in the interacting residues. These structures illustrate the flexibility of binding to sequences outside of-but adjacent to-the kinase domain of TrkA. This knowledge allows development of compounds with specificity for TrkA or the family of Trk proteins., Competing Interests: The work described in this manuscript was performed while all authors were employed at Merck and Co., Inc.
- Published
- 2017
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9. Potent, selective and orally bioavailable leucine-rich repeat kinase 2 (LRRK2) inhibitors.
- Author
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Greshock TJ, Sanders JM, Drolet RE, Rajapakse HA, Chang RK, Kim B, Rada VL, Tiscia HE, Su H, Lai MT, Sur SM, Sanchez RI, Bilodeau MT, Renger JJ, Kern JT, and McCauley JA
- Subjects
- Administration, Oral, Biological Availability, Dose-Response Relationship, Drug, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 metabolism, Molecular Docking Simulation, Molecular Structure, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemistry, Structure-Activity Relationship, Thiophenes chemical synthesis, Thiophenes chemistry, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Thiophenes pharmacology
- Abstract
Familial Parkinson's disease cases have recently been associated with the leucine rich repeat kinase 2 (LRRK2) gene. It has been hypothesized that inhibition of the LRRK2 protein may have the potential to alter disease pathogenesis. A dihydrobenzothiophene series of potent, selective, orally bioavailable LRRK2 inhibitors were identified from a high-throughput screen of the internal Merck sample collection. Initial SAR studies around the core established the series as a tractable small molecule lead series of LRRK2 inhibitors for potential treatment of Parkinson's disease. It was also found that incorporation of a lactam into the core drastically improved the CNS and DMPK properties of these small molecules., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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10. Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer's Disease.
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Stachel SJ, Zerbinatti C, Rudd MT, Cosden M, Suon S, Nanda KK, Wessner K, DiMuzio J, Maxwell J, Wu Z, Uslaner JM, Michener MS, Szczerba P, Brnardic E, Rada V, Kim Y, Meissner R, Wuelfing P, Yuan Y, Ballard J, Holahan M, Klein DJ, Lu J, Fradera X, Parthasarathy G, Uebele VN, Chen Z, Li Y, Li J, Cooke AJ, Bennett DJ, Bilodeau MT, and Renger J
- Subjects
- Animals, Brain drug effects, Brain metabolism, Dogs, Hep G2 Cells, Humans, Lipids analysis, Liver drug effects, Liver metabolism, Liver X Receptors, Locomotion drug effects, Macaca mulatta, Madin Darby Canine Kidney Cells, Mice, Mice, Transgenic, ATP-Binding Cassette Transporters metabolism, Alzheimer Disease drug therapy, Amyloid beta-Peptides cerebrospinal fluid, Apolipoproteins E cerebrospinal fluid, Benzamides chemistry, Benzamides pharmacology, Orphan Nuclear Receptors agonists, Piperidines chemistry, Piperidines pharmacology
- Abstract
Herein, we describe the development of a functionally selective liver X receptor β (LXRβ) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-β peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity.
- Published
- 2016
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11. Simple method provides resolution of albumin, lipoprotein, free fraction, and chylomicron to enhance the utility of protein binding assays.
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Brockman AH, Oller HR, Moreau B, Kriksciukaite K, and Bilodeau MT
- Subjects
- Bridged-Ring Compounds chemistry, Chemistry, Pharmaceutical, Dialysis, Molecular Structure, Organoplatinum Compounds chemistry, Protein Binding, Taxoids chemistry, Albumins chemistry, Lipoproteins chemistry, Ultracentrifugation
- Abstract
Medicinal chemists have been encouraged in recent years to embrace high speed protein binding assays. These methods employ dialysis membranes in 96-well format or spin filters. Membrane-based methods do not separate lipoprotein binding from albumin binding and introduce interference despite membrane binding controls. Ultracentrifugation methods, in contrast, do not introduce interference if density gradients can be avoided and they resolve lipoprotein from albumin. A new generation of compact, fast ultracentrifuges facilitates the rapid and fully informative separation of plasma into albumin, albumin/fatty acid complex, lipoprotein, protein-free, and chylomicron fractions with no need of salt or sugar density gradients. We present a simple and fast ultracentrifuge method here for two platinum compounds and a taxane that otherwise bound irreversibly to dialysis membranes and which exhibited distinctive lipoprotein binding behaviors. This new generation of ultracentrifugation methods underscores a need to further discuss protein binding assessments as they relate to medicinal chemistry efforts.
- Published
- 2015
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12. Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.
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Stachel SJ, Sanders JM, Henze DA, Rudd MT, Su HP, Li Y, Nanda KK, Egbertson MS, Manley PJ, Jones KL, Brnardic EJ, Green A, Grobler JA, Hanney B, Leitl M, Lai MT, Munshi V, Murphy D, Rickert K, Riley D, Krasowska-Zoladek A, Daley C, Zuck P, Kane SA, and Bilodeau MT
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- Animals, Drug Evaluation, Preclinical, Humans, Indoles chemistry, Indoles pharmacokinetics, Ligands, Models, Molecular, Protein Kinase Inhibitors pharmacokinetics, Pyrimidines chemistry, Pyrimidines pharmacokinetics, Rats, Small Molecule Libraries therapeutic use, Structure-Activity Relationship, Triazoles chemistry, Triazoles pharmacokinetics, Urea analogs & derivatives, Urea chemistry, Urea pharmacokinetics, Chronic Pain drug therapy, Protein Kinase Inhibitors chemistry, Receptor, trkA antagonists & inhibitors
- Abstract
We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.
- Published
- 2014
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13. Identification of a methoxynaphthalene scaffold as a core replacement in quinolizidinone amide M(1) positive allosteric modulators.
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Kuduk SD, Di Marco CN, Saffold JR, Ray WJ, Ma L, Wittmann M, Koeplinger KA, Thompson CD, Hartman GD, Bilodeau MT, and Beshore DC
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- Allosteric Regulation, Amides chemical synthesis, Amides metabolism, Animals, CHO Cells, Cricetinae, Cricetulus, Mice, Protein Binding, Receptor, Muscarinic M1 chemistry, Structure-Activity Relationship, Amides chemistry, Naphthalenes chemistry, Quinolizidines chemistry, Receptor, Muscarinic M1 metabolism
- Abstract
A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M1 positive allosteric modulators. A methoxy group was optimal for M1 activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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14. Discovery of naphthyl-fused 5-membered lactams as a new class of m1 positive allosteric modulators.
- Author
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Yang ZQ, Shu Y, Ma L, Wittmann M, Ray WJ, Seager MA, Koeplinger KA, Thompson CD, Hartman GD, Bilodeau MT, and Kuduk SD
- Abstract
Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an original approach to treat the cognitive decline in patients with Alzheimer's disease. A series of naphthyl-fused 5-membered lactams were identified as a new class of M1 positive allosteric modulators and were found to possess good potency and in vivo efficacy.
- Published
- 2014
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15. Benzimidazole CB2 agonists: design, synthesis and SAR.
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Nanda KK, Henze DA, Della Penna K, Desai R, Leitl M, Lemaire W, White RB, Yeh S, Brouillette JN, Hartman GD, Bilodeau MT, and Trotter BW
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- Benzimidazoles chemical synthesis, Benzimidazoles chemistry, Dose-Response Relationship, Drug, Humans, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Benzimidazoles pharmacology, Drug Design, Receptor, Cannabinoid, CB2 agonists
- Abstract
A new series of CB2-selective agonists containing a benzimidazole core is reported. Design, synthesis, SAR and pharmacokinetic data for selected compounds are described., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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16. Identification of amides as carboxylic Acid surrogates for quinolizidinone-based m1 positive allosteric modulators.
- Author
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Kuduk SD, Chang RK, Greshock TJ, Ray WJ, Ma L, Wittmann M, Seager MA, Koeplinger KA, Thompson CD, Hartman GD, and Bilodeau MT
- Abstract
Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an approach to treat the cognitive decline in patients with Alzheimer's disease. A series of amides were examined as a replacement for the carboxylic acid moiety in a class of quinolizidinone carboxylic acid M1 muscarinic receptor positive allosteric modulators, and leading pyran 4o and cyclohexane 5c were found to possess good potency and in vivo efficacy.
- Published
- 2012
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17. Identification of non-amidine inhibitors of acid-sensing ion channel-3 (ASIC3).
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Kuduk SD, Chang RK, Di Marco CN, Dipardo RM, Cook SP, Cato MJ, Jovanovska A, Urban MO, Leitl M, Spencer RH, Kane SA, Hartman GD, and Bilodeau MT
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- Acid Sensing Ion Channels, Amidines chemistry, Amiloride chemistry, Animals, Nerve Tissue Proteins metabolism, Rats, Sodium Channel Blockers pharmacology, Sodium Channels metabolism, Structure-Activity Relationship, Nerve Tissue Proteins antagonists & inhibitors, Sodium Channel Blockers chemistry
- Abstract
A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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18. Discovery of a selective allosteric M1 receptor modulator with suitable development properties based on a quinolizidinone carboxylic acid scaffold.
- Author
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Kuduk SD, Chang RK, Di Marco CN, Pitts DR, Greshock TJ, Ma L, Wittmann M, Seager MA, Koeplinger KA, Thompson CD, Hartman GD, Bilodeau MT, and Ray WJ
- Subjects
- Allosteric Regulation, Animals, Biological Availability, CHO Cells, Cholinergic Agents chemistry, Cholinergic Agents pharmacology, Cricetinae, Cricetulus, Fear drug effects, Humans, Male, Mice, Nitriles chemistry, Nitriles pharmacology, Nootropic Agents chemistry, Nootropic Agents pharmacology, Piperidines chemistry, Piperidines pharmacology, Quinolizidines chemistry, Quinolizidines pharmacology, Quinolizines chemistry, Quinolizines pharmacology, Structure-Activity Relationship, Cholinergic Agents chemical synthesis, Nitriles chemical synthesis, Nootropic Agents chemical synthesis, Piperidines chemical synthesis, Quinolizidines chemical synthesis, Quinolizines chemical synthesis, Receptor, Muscarinic M1 physiology
- Abstract
One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M(1) muscarinic receptor. A number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M(2) to M(5) subtypes. One strategy to confer selectivity for M(1) is the identification of positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M(1) positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.
- Published
- 2011
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19. Fused heterocyclic M1 positive allosteric modulators.
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Kuduk SD, Di Marco CN, Cofre V, Ray WJ, Ma L, Wittmann M, Seager MA, Koeplinger KA, Thompson CD, Hartman GD, and Bilodeau MT
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 blood, ATP Binding Cassette Transporter, Subfamily B, Member 1 cerebrospinal fluid, Allosteric Regulation drug effects, Animals, Carboxylic Acids chemistry, Carboxylic Acids pharmacology, Humans, Molecular Structure, Naphthols pharmacology, Quinolones chemistry, Quinolones pharmacology, Rats, Structure-Activity Relationship, Naphthols chemistry, Receptor, Muscarinic M1 metabolism
- Abstract
Fused aromatics such as naphthalene were identified as highly potent and CNS penetrant M(1) positive allosteric modulators during an SAR study to replace the phenyl B-ring linkage., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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20. Decahydroquinoline amides as highly selective CB2 agonists: role of selectivity on in vivo efficacy in a rodent model of analgesia.
- Author
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Manley PJ, Zartman A, Paone DV, Burgey CS, Henze DA, Della Penna K, Desai R, Leitl MD, Lemaire W, White RB, Yeh S, Urban MO, Kane SA, Hartman GD, Bilodeau MT, and Trotter BW
- Subjects
- Amides chemical synthesis, Amides therapeutic use, Analgesics chemical synthesis, Analgesics therapeutic use, Animals, Disease Models, Animal, Humans, Mice, Mice, Transgenic, Pain drug therapy, Rats, Receptor, Cannabinoid, CB1 agonists, Receptor, Cannabinoid, CB1 metabolism, Receptor, Cannabinoid, CB2 metabolism, Structure-Activity Relationship, Amides chemistry, Analgesics chemistry, Quinolines chemistry, Receptor, Cannabinoid, CB2 agonists
- Abstract
A novel series of decahydroquinoline CB2 agonists is described. Optimization of the amide substituent led to improvements in CB2/CB1 selectivity as well as physical properties. Two key compounds were examined in the rat CFA model of acute inflammatory pain. A moderately selective CB2 agonist was active in this model. A CB2 agonist lacking functional CB1 activity was inactive in this model despite high in vivo exposure both peripherally and centrally., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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21. Imidazopyridine CB2 agonists: optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy.
- Author
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Trotter BW, Nanda KK, Burgey CS, Potteiger CM, Deng JZ, Green AI, Hartnett JC, Kett NR, Wu Z, Henze DA, Della Penna K, Desai R, Leitl MD, Lemaire W, White RB, Yeh S, Urban MO, Kane SA, Hartman GD, and Bilodeau MT
- Subjects
- Analgesics chemical synthesis, Analgesics therapeutic use, Animals, Disease Models, Animal, Freund's Adjuvant pharmacology, Humans, Hyperalgesia drug therapy, Pyridines chemical synthesis, Pyridines therapeutic use, Rats, Receptor, Cannabinoid, CB1 metabolism, Receptor, Cannabinoid, CB2 metabolism, Analgesics chemistry, Pyridines chemistry, Receptor, Cannabinoid, CB1 agonists, Receptor, Cannabinoid, CB2 agonists
- Abstract
A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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22. Quinolizidinone carboxylic acid selective M1 allosteric modulators: SAR in the piperidine series.
- Author
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Kuduk SD, Chang RK, Di Marco CN, Ray WJ, Ma L, Wittmann M, Seager MA, Koeplinger KA, Thompson CD, Hartman GD, and Bilodeau MT
- Subjects
- Allosteric Regulation, Animals, CHO Cells, Cricetinae, Cricetulus, Dose-Response Relationship, Drug, Piperidines metabolism, Structure-Activity Relationship, Piperidines pharmacology
- Abstract
SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M(1) positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
23. Synthesis and evaluation of a new series of Neuropeptide S receptor antagonists.
- Author
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Melamed JY, Zartman AE, Kett NR, Gotter AL, Uebele VN, Reiss DR, Condra CL, Fandozzi C, Lubbers LS, Rowe BA, McGaughey GB, Henault M, Stocco R, Renger JJ, Hartman GD, Bilodeau MT, and Trotter BW
- Subjects
- Amides chemical synthesis, Amides chemistry, Amides pharmacology, Animals, Blood-Brain Barrier metabolism, Central Nervous System metabolism, Humans, Iodine Radioisotopes chemistry, Protein Binding, Quinolones chemical synthesis, Quinolones chemistry, Quinolones pharmacology, Rats, Receptors, Neuropeptide metabolism, Structure-Activity Relationship, Receptors, Neuropeptide antagonists & inhibitors
- Abstract
Administration of Neuropeptide S (NPS) has been shown to produce arousal, that is, independent of novelty and to induce wakefulness by suppressing all stages of sleep, as demonstrated by EEG recordings in rat. Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood-brain barrier. We detail here optimization efforts resulting in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited (125)I-NPS binding in the CNS when administered to rats., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
24. Tricyclic imidazole antagonists of the Neuropeptide S Receptor.
- Author
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Trotter BW, Nanda KK, Manley PJ, Uebele VN, Condra CL, Gotter AL, Menzel K, Henault M, Stocco R, Renger JJ, Hartman GD, and Bilodeau MT
- Subjects
- Animals, Heterocyclic Compounds, 3-Ring chemical synthesis, Heterocyclic Compounds, 3-Ring pharmacology, High-Throughput Screening Assays, Humans, Imidazoles chemical synthesis, Imidazoles pharmacology, Rats, Receptors, Neuropeptide metabolism, Structure-Activity Relationship, Heterocyclic Compounds, 3-Ring chemistry, Imidazoles chemistry, Receptors, Neuropeptide antagonists & inhibitors
- Abstract
A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
25. Quinolizidinone carboxylic acids as CNS penetrant, selective m1 allosteric muscarinic receptor modulators.
- Author
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Kuduk SD, Chang RK, Di Marco CN, Ray WJ, Ma L, Wittmann M, Seager MA, Koeplinger KA, Thompson CD, Hartman GD, and Bilodeau MT
- Abstract
Positive allosteric modulation of the M1 muscarinic receptor represents an approach to treat the cognitive decline in patients with Alzheimer's disease. Replacement of a quinolone ring system in a quinolone carboxylic acid series of M1 modulators with a quinolizidinone bearing a basic amine linkage led to a series of compounds with higher free fraction, enhanced CNS exposure, and improved efficacy in rodent in vivo models of cognition.
- Published
- 2010
- Full Text
- View/download PDF
26. Heterocyclic fused pyridone carboxylic acid M(1) positive allosteric modulators.
- Author
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Kuduk SD, Di Marco CN, Chang RK, Ray WJ, Ma L, Wittmann M, Seager MA, Koeplinger KA, Thompson CD, Hartman GD, and Bilodeau MT
- Subjects
- Allosteric Regulation, Animals, Blood Proteins chemistry, Carboxylic Acids chemistry, Carboxylic Acids pharmacokinetics, Heterocyclic Compounds chemistry, Heterocyclic Compounds pharmacokinetics, Humans, Rats, Carboxylic Acids pharmacology, Heterocyclic Compounds pharmacology, Pyridones chemistry
- Abstract
The phenyl ring in a series of quinolone carboxylic acid M(1) positive allosteric modulators was replaced with a variety of heterocycles in order to reduce protein plasma binding and enhance CNS exposure., (Copyright 2010. Published by Elsevier Ltd.)
- Published
- 2010
- Full Text
- View/download PDF
27. Hydroxy cycloalkyl fused pyridone carboxylic acid M(1) positive allosteric modulators.
- Author
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Kuduk SD, DiPardo RM, Beshore DC, Ray WJ, Ma L, Wittmann M, Seager MA, Koeplinger KA, Thompson CD, Hartman GD, and Bilodeau MT
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Allosteric Regulation, Animals, Carboxylic Acids chemistry, Mice, Protein Transport, Rats, Carboxylic Acids pharmacology, Pyridones chemistry
- Abstract
Incorporation of hydroxycycloalkyl fused pyridone carboxylic acids in lieu of quinolone carboxylic acids enhance free fraction without increased susceptibility to P-glycoprotein transport., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
28. N-heterocyclic derived M1 positive allosteric modulators.
- Author
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Kuduk SD, Di Marco CN, Cofre V, Pitts DR, Ray WJ, Ma L, Wittmann M, Veng L, Seager MA, Koeplinger K, Thompson CD, Hartman GD, and Bilodeau MT
- Subjects
- Allosteric Regulation, Animals, CHO Cells, Carboxylic Acids chemistry, Carboxylic Acids pharmacology, Cell Line, Cricetinae, Cricetulus, Heterocyclic Compounds chemistry, Heterocyclic Compounds pharmacology, Humans, Molecular Structure, Pyrazoles chemistry, Pyrazoles pharmacology, Quinolines chemistry, Quinolines pharmacology, Rats, Structure-Activity Relationship, Carboxylic Acids chemical synthesis, Heterocyclic Compounds chemical synthesis, Pyrazoles chemical synthesis, Quinolines chemical synthesis
- Abstract
Replacement of a phenyl ring with N-linked heterocycles in a series of quinolone carboxylic acid M1 positive allosteric modulators was investigated. In particular, a pyrazole derivative exhibited improvements in potency, free fraction, and CNS exposure., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
29. Synthesis, structure-activity relationship, and pharmacological profile of analogs of the ASIC-3 inhibitor A-317567.
- Author
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Kuduk SD, Di Marco CN, Bodmer-Narkevitch V, Cook SP, Cato MJ, Jovanovska A, Urban MO, Leitl M, Sain N, Liang A, Spencer RH, Kane SA, Hartman GD, and Bilodeau MT
- Subjects
- Acid Sensing Ion Channels biosynthesis, Animals, Behavior, Animal drug effects, Electrophysiological Phenomena, Freund's Adjuvant, Iodoacetates, Male, Mice, Neurons drug effects, Neurons metabolism, Osteoarthritis chemically induced, Osteoarthritis drug therapy, Pain chemically induced, Pain drug therapy, Pain Measurement drug effects, Physical Stimulation, Postural Balance drug effects, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Acid Sensing Ion Channel Blockers chemical synthesis, Acid Sensing Ion Channel Blockers pharmacology, Acid Sensing Ion Channels drug effects, Analgesics chemical synthesis, Analgesics pharmacology, Isoquinolines chemical synthesis, Isoquinolines pharmacology, Naphthalenes chemical synthesis, Naphthalenes pharmacology
- Abstract
The synthesis, structure-activity relationship (SAR), and pharmacological evaluation of analogs of the acid-sensing ion channel (ASIC) inhibitor A-317567 are reported. It was found that the compound with an acetylenic linkage was the most potent ASIC-3 channel blocker. This compound reversed mechanical hypersensitivity in the rat iodoacetate model of osteoarthritis pain, although sedation was noted. Sedation was also observed in ASIC-3 knockout mice, questioning whether sedation and antinociception are mediated via a non-ASIC-3 specific mechanism.
- Published
- 2010
- Full Text
- View/download PDF
30. Pyridine containing M(1) positive allosteric modulators with reduced plasma protein binding.
- Author
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Kuduk SD, Di Marco CN, Cofre V, Pitts DR, Ray WJ, Ma L, Wittmann M, Seager MA, Koeplinger K, Thompson CD, Hartman GD, and Bilodeau MT
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Allosteric Regulation, Animals, Blood Proteins metabolism, Humans, Protein Binding, Pyridines chemical synthesis, Pyridines pharmacology, Rats, Receptor, Muscarinic M1 metabolism, Structure-Activity Relationship, Blood Proteins chemistry, Pyridines chemistry, Receptor, Muscarinic M1 antagonists & inhibitors
- Abstract
Incorporation of pyridines and diazines into the biphenyl region of quinolone carboxylic acid derived M(1) positive allosteric modulators was investigated as a means of lowering plasma protein binding to enhance CNS exposure., (Copyright 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
31. Amidine derived inhibitors of acid-sensing ion channel-3 (ASIC3).
- Author
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Kuduk SD, Chang RK, Wai JM, Di Marco CN, Cofre V, DiPardo RM, Cook SP, Cato MJ, Jovanovska A, Urban MO, Leitl M, Spencer RH, Kane SA, Hartman GD, and Bilodeau MT
- Subjects
- Acid Sensing Ion Channels, Animals, Drug Design, Electrophysiology, Indoles chemistry, Inhibitory Concentration 50, Ion Channels chemistry, Male, Models, Chemical, Naproxen pharmacology, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Amidines chemistry, Chemistry, Pharmaceutical methods, Sodium Channels chemistry
- Abstract
A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.
- Published
- 2009
- Full Text
- View/download PDF
32. Kv1.5 blockers for the treatment of atrial fibrillation: approaches to optimization of potency and selectivity and translation to in vivo pharmacology.
- Author
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Bilodeau MT and Trotter BW
- Subjects
- Animals, Atrial Fibrillation metabolism, Clinical Trials as Topic, Drug Evaluation, Preclinical, Humans, Molecular Structure, Potassium Channel Blockers administration & dosage, Potassium Channel Blockers chemistry, Potassium Channel Blockers pharmacology, Structure-Activity Relationship, Substrate Specificity, Atrial Fibrillation drug therapy, Drug Design, Kv1.5 Potassium Channel antagonists & inhibitors, Potassium Channel Blockers therapeutic use
- Abstract
The treatment and prevention of atrial fibrillation (AF) remains a significant unmet medical need. Existing therapies that maintain or restore sinus rhythm (rhythm control) have deleterious effects on the ventricle. A major goal for finding new AF therapies is the identification of repolarization mechanisms that are present in the atrium and not in the ventricle. The potassium current I(Kur) has been shown to be selectively involved in atrial repolarization in human tissue. Hence this current and specifically Kv1.5, the protein that underlies it, have become prime targets for the invention of new AF agents. This article reviews the development of Kv1.5 blockers. The discovery and clinical progress of the non-selective Kv1.5 blockers vernakalant and AVE-0118 are highlighted. More selective Kv1.5 blockers in pre-clinical stages of discovery are then reviewed, with a focus on compounds that have been investigated for their in vivo effects on atrial repolarization or on efficacy in pre-clinical models of atrial fibrillation.
- Published
- 2009
- Full Text
- View/download PDF
33. Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model.
- Author
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Bilodeau MT, Balitza AE, Hoffman JM, Manley PJ, Barnett SF, Defeo-Jones D, Haskell K, Jones RE, Leander K, Robinson RG, Smith AM, Huber HE, and Hartman GD
- Subjects
- Animals, Antineoplastic Agents chemistry, Combinatorial Chemistry Techniques, Disease Models, Animal, Drug Design, Drug Screening Assays, Antitumor, Humans, Mice, Naphthyridines chemistry, Proto-Oncogene Proteins c-akt metabolism, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Naphthyridines chemical synthesis, Naphthyridines pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors
- Abstract
A series of naphthyridine and naphthyridinone allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been optimized to have potent dual activity against the activated kinase as well as the activation of Akt in cells. One molecule in particular, compound 17, has potent inhibitory activity against Akt1 and 2 in vivo in a mouse lung and efficacy in a tumor xenograft model.
- Published
- 2008
- Full Text
- View/download PDF
34. Optimization of 2,3,5-trisubstituted pyridine derivatives as potent allosteric Akt1 and Akt2 inhibitors.
- Author
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Hartnett JC, Barnett SF, Bilodeau MT, Defeo-Jones D, Hartman GD, Huber HE, Jones RE, Kral AM, Robinson RG, and Wu Z
- Subjects
- Animals, Apoptosis drug effects, Caspases metabolism, Dogs, Humans, Male, Metabolic Clearance Rate, Molecular Structure, Prostatic Neoplasms metabolism, Protein Kinase Inhibitors chemical synthesis, Proto-Oncogene Proteins c-akt metabolism, Structure-Activity Relationship, TNF-Related Apoptosis-Inducing Ligand pharmacology, Tumor Cells, Cultured, Allosteric Site, Prostatic Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Pyridines chemistry
- Abstract
This letter shows inhibitor SAR on a pyridine series of allosteric Akt inhibitors to optimize enzymatic and cellular potency. We have optimized 2,3,5-trisubstituted pyridines to give potent Akt1 and Akt2 inhibitors in both enzyme and cell based assays. In addition, we will also highlight the pharmacokinetic profile of an optimized inhibitor that has low clearance and long half-life in dogs.
- Published
- 2008
- Full Text
- View/download PDF
35. Rapid assembly of diverse and potent allosteric Akt inhibitors.
- Author
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Wu Z, Robinson RG, Fu S, Barnett SF, Defeo-Jones D, Jones RE, Kral AM, Huber HE, Kohl NE, Hartman GD, and Bilodeau MT
- Subjects
- Animals, Apoptosis drug effects, Caspases metabolism, Dogs, Female, Humans, Male, Metabolic Clearance Rate, Molecular Structure, Ovarian Neoplasms metabolism, Phosphorylation drug effects, Prostatic Neoplasms metabolism, Protein Kinase Inhibitors pharmacokinetics, Proto-Oncogene Proteins c-akt metabolism, Structure-Activity Relationship, TNF-Related Apoptosis-Inducing Ligand pharmacology, Tumor Cells, Cultured, Allosteric Site, Ovarian Neoplasms drug therapy, Prostatic Neoplasms drug therapy, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Pyridines chemistry, Pyrimidines chemistry
- Abstract
This paper describes the rapid assembly of four different classes of potent Akt inhibitors from a common intermediate. Among them, a pyridopyrimidine series displayed the best intrinsic and cell potency against Akt1 and Akt2. This series also showed a promising pharmacokinetic profile and excellent selectivity over other closely related kinases.
- Published
- 2008
- Full Text
- View/download PDF
36. Development of pyridopyrimidines as potent Akt1/2 inhibitors.
- Author
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Wu Z, Hartnett JC, Neilson LA, Robinson RG, Fu S, Barnett SF, Defeo-Jones D, Jones RE, Kral AM, Huber HE, Hartman GD, and Bilodeau MT
- Subjects
- Amines chemical synthesis, Amines chemistry, Amines pharmacology, Caspase 3 metabolism, Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Inhibitory Concentration 50, Piperidines chemical synthesis, Piperidines chemistry, Piperidines pharmacology, Protein Kinase Inhibitors chemistry, Pyrimidines chemistry, Structure-Activity Relationship, TNF-Related Apoptosis-Inducing Ligand pharmacology, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Pyrimidines chemical synthesis, Pyrimidines pharmacology
- Abstract
This communication reports a new synthetic route of pyridopyrimidines to facilitate their structural optimization in a library fashion and describes the development of pyridopyrimidines that have excellent enzymatic and cell potency against Akt1 and Akt2. This series also shows a high level of selectivity over other closely related kinases and significantly improved caspase-3 activity with the more optimized compounds.
- Published
- 2008
- Full Text
- View/download PDF
37. The PI3K/Akt pathway: recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors.
- Author
-
Lindsley CW, Barnett SF, Layton ME, and Bilodeau MT
- Subjects
- Allosteric Regulation drug effects, Allosteric Regulation physiology, Animals, Enzyme Inhibitors pharmacology, Humans, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects, Technology, Pharmaceutical trends, Adenosine Triphosphate metabolism, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Signal Transduction physiology
- Abstract
This article describes recent advances in the development and biological evaluation of allosteric and ATP-competitive small molecule inhibitors for the serine/threonine kinase Akt (protein kinase B, PKB). Unregulated activation of the PI3K/Akt/PTEN pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers making Akt an exciting new target for cancer therapy. The development of Akt inhibitors has been complicated and hampered by the presence of three Akt isozymes, (Akt1, Akt2 and Akt3) which differ in function and tissue distribution, as well as a lack of Akt specific inhibitors. In the past 18 months, a large number of reports have appeared describing the discovery and development of allosteric Akt kinase inhibitors and classical ATP-competitive Akt kinase inhibitors. This review will discuss the PI3K/Akt/PTEN pathway, allosteric and ATP-competitive Akt kinase inhibitors, their biological evaluation and progress towards target validation.
- Published
- 2008
- Full Text
- View/download PDF
38. The impact of I(Kr) blockade on medicinal chemistry programs.
- Author
-
Bell IM and Bilodeau MT
- Subjects
- Animals, Drug Evaluation, Preclinical, Ether-A-Go-Go Potassium Channels chemistry, Farnesyltranstransferase antagonists & inhibitors, Farnesyltranstransferase metabolism, Humans, Protein Kinase Inhibitors chemistry, Receptors, N-Methyl-D-Aspartate chemistry, Receptors, N-Methyl-D-Aspartate metabolism, Chemistry, Pharmaceutical trends, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Ether-A-Go-Go Potassium Channels metabolism
- Abstract
Inhibition of the cardiac I(Kr) current leads to prolongation of the QT interval and to a risk of ventricular arrhythmia. This activity has been observed for a wide range of small molecules and results from their binding to the hERG ion channel. The off-target inhibition of I(Kr) presents a daunting challenge for many medicinal chemistry programs. This review article presents case studies that describe a rang of findings across several projects at Merck. The article begins with a review of findings from the original efforts to identify I(Kr) blockers as antiarrhythmic therapeutics. A discussion follows of in vitro and in vivo assays that have been utilized for the assessment of I(Kr) inhibition. General SAR rules that have been found to be useful guides for diminishing hERG activity in lead compounds are discussed and case studies are presented that illustrate specific observations. The case studies highlight how the issue of hERG antagonism was navigated on four distinct medicinal chemistry programs.
- Published
- 2008
- Full Text
- View/download PDF
39. Recent progress in the development of ATP-competitive and allosteric Akt kinase inhibitors.
- Author
-
Lindsley CW, Barnett SF, Yaroschak M, Bilodeau MT, and Layton ME
- Subjects
- Allosteric Regulation drug effects, Antineoplastic Agents chemistry, Binding, Competitive, Drug Design, Humans, Protein Kinase Inhibitors pharmacology, Adenosine Triphosphate antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins c-akt antagonists & inhibitors
- Abstract
This article describes recent advances in the development and biological evaluation of small molecule inhibitors for the serine/threonine kinase Akt (PKB). Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the PI3K/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers. Akt is considered an attractive target for cancer therapy and inhibition of Akt alone or in combination with standard cancer chemotherapeutics has been postulated to reduce the apoptotic threshold and preferentially kill cancer cells. The development of specific and potent inhibitors will allow this hypothesis to be tested in animals. Recently, several series of small molecule, ATP-competitive inhibitors have been reported with a range of Akt potencies and selectivities. Phosphatidylinositol (PI) analogs have been reported to inhibit Akt, but these inhibitors may also have specificity problems with respect to other pleckstrin homology (PH) domain containing proteins and may have poor bioavailability. In addition, novel allosteric inhibitors have been reported which are PH domain dependent, exhibit selectivity for the individual Akt isozymes and inhibit the activity and the activation of Akt. Compounds within these classes Akt inhibitors have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed.
- Published
- 2007
- Full Text
- View/download PDF
40. Potent antagonists of the Kv1.5 potassium channel: synthesis and evaluation of analogous N,N-diisopropyl-2-(pyridine-3-yl)acetamides.
- Author
-
Nanda KK, Nolt MB, Cato MJ, Kane SA, Kiss L, Spencer RH, Wang J, Lynch JJ, Regan CP, Stump GL, Li B, White R, Yeh S, Bogusky MJ, Bilodeau MT, Dinsmore CJ, Lindsley CW, Hartman GD, Wolkenberg SE, and Trotter BW
- Subjects
- Animals, Dogs, Stereoisomerism, Structure-Activity Relationship, Time Factors, Urea chemical synthesis, Urea pharmacology, Acetamides chemical synthesis, Acetamides pharmacology, Kv1.5 Potassium Channel antagonists & inhibitors, Potassium Channel Blockers chemical synthesis, Potassium Channel Blockers pharmacology, Pyridines chemical synthesis, Pyridines pharmacology, Urea analogs & derivatives
- Abstract
This letter describes the discovery of a novel series of potent Kv1.5 ion channel antagonists based on a diisopropyl amide scaffold. Structure-activity relationships of functionalized analogs are discussed. Key compound 1-(3-(diisopropylcarbamoyl)-2-phenyl-3-(pyridin-3-yl)propyl)-3-(2-fluorobenzyl)urea (10) exhibits significant atrial-selective effects in an in vivo model.
- Published
- 2006
- Full Text
- View/download PDF
41. Potent 2-[(pyrimidin-4-yl)amine}-1,3-thiazole-5-carbonitrile-based inhibitors of VEGFR-2 (KDR) kinase.
- Author
-
Sisko JT, Tucker TJ, Bilodeau MT, Buser CA, Ciecko PA, Coll KE, Fernandes C, Gibbs JB, Koester TJ, Kohl N, Lynch JJ, Mao X, McLoughlin D, Miller-Stein CM, Rodman LD, Rickert KW, Sepp-Lorenzino L, Shipman JM, Thomas KA, Wong BK, and Hartman GD
- Subjects
- Animals, Dogs, Macaca mulatta, Molecular Structure, Nitriles chemistry, Protein Kinase Inhibitors chemistry, Pyrimidines chemistry, Rats, Sensitivity and Specificity, Structure-Activity Relationship, Thiazoles chemistry, Vascular Endothelial Growth Factor Receptor-2 metabolism, Nitriles chemical synthesis, Nitriles pharmacology, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Pyrimidines chemical synthesis, Pyrimidines pharmacology, Thiazoles chemical synthesis, Thiazoles pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
Pyrimidino-thiazolyl carbonitriles were prepared that are potent VEGFR-2 (KDR) kinase inhibitors. The modification of lead structures resulted in 3m which exhibited the best overall profile in KDR inhibitory activity, iv/po pharmacokinetics, and reduced hERG affinity.
- Published
- 2006
- Full Text
- View/download PDF
42. The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation.
- Author
-
Barnett SF, Bilodeau MT, and Lindsley CW
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Humans, Proto-Oncogene Proteins c-akt, Structure-Activity Relationship, Enzyme Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Proto-Oncogene Proteins antagonists & inhibitors
- Abstract
This article describes recent advances in the development and biological evaluation of small molecule inhibitors for the serine/threonine kinase Akt (PKB). Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the PI3K/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers. Akt is considered an attractive target for chemotherapy and it has been postulated that inhibition of Akt alone or in combination with standard cancer chemotherapeutics will reduce the apoptotic threshold and preferentially kill cancer cells. The development of specific and potent inhibitors will allow this hypothesis to be tested in animals. The majority of small molecule inhibitors in this nascent field are classic ATP-competitive inhibitors which provide little specificity. Phosphatidylinositol (PI) analogs have been reported to inhibit Akt, but these inhibitors may also have specificity problems with respect to other PH domain containing proteins and may have poor bioavailability. None of the inhibitors in these classes have been reported to have Akt isozyme specificity. Recently, novel allosteric inhibitors have been reported which are pleckstrin homology domain dependent and exhibit Akt isozyme selectivity. Inhibitors in this class may have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed.
- Published
- 2005
- Full Text
- View/download PDF
43. Potent N-(1,3-thiazol-2-yl)pyridin-2-amine vascular endothelial growth factor receptor tyrosine kinase inhibitors with excellent pharmacokinetics and low affinity for the hERG ion channel.
- Author
-
Bilodeau MT, Balitza AE, Koester TJ, Manley PJ, Rodman LD, Buser-Doepner C, Coll KE, Fernandes C, Gibbs JB, Heimbrook DC, Huckle WR, Kohl N, Lynch JJ, Mao X, McFall RC, McLoughlin D, Miller-Stein CM, Rickert KW, Sepp-Lorenzino L, Shipman JM, Subramanian R, Thomas KA, Wong BK, Yu S, and Hartman GD
- Subjects
- Administration, Oral, Aminopyridines pharmacokinetics, Aminopyridines pharmacology, Animals, Biological Availability, Cell Line, Dogs, ERG1 Potassium Channel, Electrocardiography drug effects, Ether-A-Go-Go Potassium Channels, In Vitro Techniques, Lung enzymology, Macaca mulatta, Male, Mice, Microsomes, Liver metabolism, Phosphorylation, Pyridines pharmacokinetics, Pyridines pharmacology, Radioligand Assay, Rats, Rats, Sprague-Dawley, Thiazoles pharmacokinetics, Thiazoles pharmacology, Tissue Distribution, Vascular Endothelial Growth Factor Receptor-2 metabolism, Aminopyridines chemical synthesis, Potassium Channels, Voltage-Gated metabolism, Pyridines chemical synthesis, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors, Thiazoles chemical synthesis
- Abstract
A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.
- Published
- 2004
- Full Text
- View/download PDF
44. A new synthesis of naphthyridinones and quinolinones: palladium-catalyzed amidation of o-carbonyl-substituted aryl halides.
- Author
-
Manley PJ and Bilodeau MT
- Abstract
[reaction: see text] An alternative to the Friedlander condensation for the synthesis of naphthyridinones and quinolinones has been discovered. Palladium-catalyzed amidation of halo aromatics substituted in the ortho position by a carbonyl functional group or its equivalent with primary or secondary amides leads to the formation of substituted naphthyridinones and quinolinones.
- Published
- 2004
- Full Text
- View/download PDF
45. The discovery of N-(1,3-thiazol-2-yl)pyridin-2-amines as potent inhibitors of KDR kinase.
- Author
-
Bilodeau MT, Rodman LD, McGaughey GB, Coll KE, Koester TJ, Hoffman WF, Hungate RW, Kendall RL, McFall RC, Rickert KW, Rutledge RZ, and Thomas KA
- Subjects
- Amines chemical synthesis, Binding Sites, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Humans, Inhibitory Concentration 50, Models, Molecular, Protein Binding, Protein Conformation drug effects, Structure-Activity Relationship, Thermodynamics, Vascular Endothelial Growth Factor Receptor-2 chemistry, Amines pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
An azo-dye lead was modified to a novel N-(1,3-thiazol-2-yl)pyridin-2-amine series of KDR kinase inhibitors through the use of rapid analog libraries. This new class has been found to be potent, selective, and of low molecular weight. Molecular modeling has postulated an interesting conformational preference and binding mode for these compounds in the active site of the enzyme.
- Published
- 2004
- Full Text
- View/download PDF
46. Design and synthesis of 3,7-diarylimidazopyridines as inhibitors of the VEGF-receptor KDR.
- Author
-
Wu Z, Fraley ME, Bilodeau MT, Kaufman ML, Tasber ES, Balitza AE, Hartman GD, Coll KE, Rickert K, Shipman J, Shi B, Sepp-Lorenzino L, and Thomas KA
- Subjects
- Drug Design, Humans, Molecular Structure, Solubility, Structure-Activity Relationship, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Pyridines chemical synthesis, Pyridines pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
3,7-Diarylsubstituted imidazopyridines were designed and developed as a new class of KDR kinase inhibitors. A variety of imidazopyridines were synthesized and potent inhibitors of KDR kinase activity were identified with good aqueous solubility.
- Published
- 2004
- Full Text
- View/download PDF
47. Design and synthesis of 1,5-diarylbenzimidazoles as inhibitors of the VEGF-receptor KDR.
- Author
-
Bilodeau MT, Cunningham AM, Koester TJ, Ciecko PA, Coll KE, Huckle WR, Hungate RW, Kendall RL, McFall RC, Mao X, Rutledge RZ, and Thomas KA
- Subjects
- Animals, Chemical Phenomena, Chemistry, Physical, Dogs, Drug Design, Enzyme Inhibitors pharmacokinetics, Half-Life, Hydrogen-Ion Concentration, Indicators and Reagents, Molecular Conformation, Rats, Structure-Activity Relationship, Benzimidazoles chemical synthesis, Benzimidazoles pharmacology, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
1,5-Diarylbenzimidazoles have been identified as potent inhibitors of KDR kinase activity. The series was developed with a goal of finding compounds with optimal drug-like properties. This communication describes structural modifications in the series that enhance solubility, lower protein binding, and provide compounds with excellent potency and pharmacokinetic profiles.
- Published
- 2003
- Full Text
- View/download PDF
48. 2,4-disubstituted pyrimidines: a novel class of KDR kinase inhibitors.
- Author
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Manley PJ, Balitza AE, Bilodeau MT, Coll KE, Hartman GD, McFall RC, Rickert KW, Rodman LD, and Thomas KA
- Subjects
- Angiogenesis Inhibitors pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cells, Cultured, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Humans, Inhibitory Concentration 50, Pyrimidines chemical synthesis, Structure-Activity Relationship, Angiogenesis Inhibitors chemical synthesis, Pyrimidines pharmacology, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
2,4-Disubstituted pyrimidines were synthesized as a novel class of KDR kinase inhibitors. Evaluation of the SAR of the screening lead compound 1 (KDR IC(50)=105 nM, Cell IC(50)=8% inhibition at 500 nM) led to the potent 3,5-dimethylaniline derivative 2d (KDR IC(50)=6 nM, cell IC(50)=19 nM).
- Published
- 2003
- Full Text
- View/download PDF
49. Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors: improvements in physical properties enhance cellular activity and pharmacokinetics.
- Author
-
Fraley ME, Rubino RS, Hoffman WF, Hambaugh SR, Arrington KL, Hungate RW, Bilodeau MT, Tebben AJ, Rutledge RZ, Kendall RL, McFall RC, Huckle WR, Coll KE, and Thomas KA
- Subjects
- Angiogenesis Inhibitors pharmacokinetics, Angiogenesis Inhibitors pharmacology, Animals, Cell Division drug effects, Cell Line, Endothelium, Vascular drug effects, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors pharmacology, Humans, Inhibitory Concentration 50, Metabolic Clearance Rate, Pharmacokinetics, Pyrimidines chemical synthesis, Pyrimidines pharmacology, Rats, Solubility, Structure-Activity Relationship, Angiogenesis Inhibitors chemical synthesis, Pyrimidines pharmacokinetics, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors
- Abstract
We have introduced solubilizing functionality to a 3,6-disubstituted pyrazolo[1,5-a]pyrimidine series of KDR kinase inhibitors to improve the physical properties of these compounds. The addition of a basic side-chain to the 6-aryl ring, introduction of 3-pyridyl groups, and most significantly, incorporation of a 4-pyridinonyl substituent at the 6-position of the core are modifications that maintain and often enhance the intrinsic potency of this class of inhibitors. Moreover, the improvements in physical properties result in marked increases in cellular activity and more favorable pharmacokinetics in rats. The synthesis and SAR of these compounds are described.
- Published
- 2002
- Full Text
- View/download PDF
50. A mild method for the formation and in situ reaction of imidoyl chlorides: conversion of pyridine-1-oxides to 2-aminopyridine amides.
- Author
-
Manley PJ and Bilodeau MT
- Subjects
- Chemistry, Pharmaceutical methods, Chlorides chemistry, Oxalates chemistry, Oxides chemistry, Amides chemical synthesis, Aminopyridines chemical synthesis
- Abstract
[reaction: see text] A mild, practical, one-pot method for the generation of imidoyl chlorides and their subsequent in situ reaction with pyridine-1-oxides is described. The imidoyl chlorides were formed from the reaction of secondary amides with a stoichiometric amount of oxalyl chloride and 2,6-lutidine in CH(2)Cl(2) at 0 degrees C. Upon warming of the reaction mixture to room temperature in the presence of pyridine-1-oxides, a rapid conversion to 2-aminopyridine amides was observed in moderate to excellent isolated yields.
- Published
- 2002
- Full Text
- View/download PDF
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