40 results on '"Kort ME"'
Search Results
2. A-995662 [(R)-8-(4-methyl-5-(4-(trifluoromethyl)phenyl)oxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol], a novel, selective TRPV1 receptor antagonist, reduces spinal release of glutamate and CGRP in a rat knee joint pain model.
- Author
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Puttfarcken PS, Han P, Joshi SK, Neelands TR, Gauvin DM, Baker SJ, Lewis LG, Bianchi BR, Mikusa JP, Koenig JR, Perner RJ, Kort ME, Honore P, Faltynek CR, Kym PR, Reilly RM, Puttfarcken, Pamela S, Han, Ping, Joshi, Shailen K, and Neelands, Torben R
- Published
- 2010
- Full Text
- View/download PDF
3. Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex.
- Author
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Hao Q, Rathinaswamy MK, Klinge KL, Bratkowski M, Mafi A, Baumgartner CK, Hamel KM, Veits GK, Jain R, Catalano C, Fitzgerald M, Hird AW, Park E, Vora HU, Henderson JA, Longenecker K, Hutchins CW, Qiu W, Scapin G, Sun Q, Stoll VS, Sun C, Li P, Eaton D, Stokoe D, Fisher SL, Nasveschuk CG, Paddock M, and Kort ME
- Abstract
PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4
CRBN , and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes., (© 2024. The Author(s).)- Published
- 2024
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4. Discovery of a Potent Chloroacetamide GPX4 Inhibitor with Bioavailability to Enable Target Engagement in Mice, a Potential Tool Compound for Inducing Ferroptosis In Vivo .
- Author
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Randolph JT, O'Connor MJ, Han F, Hutchins CW, Siu YA, Cho M, Zheng Y, Hickson JA, Markley JL, Manaves V, Algire M, Baker KA, Chapman AM, Gopalakrishnan SM, Panchal SC, Foster-Duke K, Stolarik DF, Kempf-Grote A, Dammeier D, Fossey S, Sun Q, Sun C, Shen Y, Dart MJ, Kati WM, Lai A, Firestone AJ, and Kort ME
- Subjects
- Mice, Animals, Phospholipid Hydroperoxide Glutathione Peroxidase metabolism, Biological Availability, Ferroptosis, Neoplasms
- Abstract
Compounds that inhibit glutathione peroxidase 4 (GPX4) hold promise as cancer therapeutics in their ability to induce a form of nonapoptotic cell death called ferroptosis. Our research identified 24 , a structural analog of the potent GPX4 inhibitor RSL3, that has much better plasma stability ( t
1/2 > 5 h in mouse plasma). The bioavailability of 24 provided efficacious plasma drug concentrations with IP dosing, thus enabling in vivo studies to assess tolerability and efficacy. An efficacy study in mouse using a GPX4-sensitive tumor model found that doses of 24 up to 50 mg/kg were tolerated for 20 days but had no effect on tumor growth, although partial target engagement was observed in tumor homogenate.- Published
- 2023
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5. Discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) and analogs as small molecule Na v 1.7/ Nav1.8 blockers for the treatment of pain.
- Author
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Patel MV, Peltier HM, Matulenko MA, Koenig JR, C Scanio MJ, Gum RJ, El-Kouhen OF, Fricano MM, Lundgaard GL, Neelands T, Zhang XF, Zhan C, Pai M, Ghoreishi-Haack N, Hudzik T, Gintant G, Martin R, McGaraughty S, Xu J, Bow D, Kalvass JC, Kym PR, DeGoey DA, and Kort ME
- Subjects
- Humans, Pain Management, Protein Isoforms, Structure-Activity Relationship, Pain drug therapy, Sodium Channels metabolism
- Abstract
The voltage-gated sodium channel Na
v 1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Nav 1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Nav 1.7 blockers with oral activity, improved selectivity, good drug-like properties, and safety led to the discovery of 2-substituted quinolines and quinolones as potent small molecule Nav 1.7 blockers. The design of these molecules focused on maintaining potency at Nav 1.7, improving selectivity over the hERG channel, and overcoming phospholipidosis observed with the initial leads. The structure-activity relationship (SAR) studies leading to the discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) are described herein. ABBV-318 displayed robust in vivo efficacy in both inflammatory and neuropathic rodent models of pain. ABBV-318 also inhibited Nav 1.8, another sodium channel isoform that is an active target for the development of new pain treatments., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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6. IL-23 induces regulatory T cell plasticity with implications for inflammatory skin diseases.
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Kannan AK, Su Z, Gauvin DM, Paulsboe SE, Duggan R, Lasko LM, Honore P, Kort ME, McGaraughty SP, Scott VE, and Gauld SB
- Subjects
- Animals, Cells, Cultured, Dermatitis pathology, Disease Models, Animal, Forkhead Transcription Factors metabolism, Interleukin-17 metabolism, Interleukin-23 administration & dosage, Mice, Mice, Inbred C57BL, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Psoriasis chemically induced, Psoriasis pathology, T-Lymphocytes, Regulatory drug effects, Cell Plasticity drug effects, Dermatitis metabolism, Interleukin-23 pharmacology, Psoriasis metabolism, T-Lymphocytes, Regulatory metabolism
- Abstract
Foxp3
+ regulatory T cells (Tregs) represent a major fraction of skin resident T cells. Although normally protective, Tregs have been shown to produce pro-inflammatory cytokines in human diseases, including psoriasis. A significant hurdle in the Treg field has been the identification, or development, of model systems to study this Treg plasticity. To overcome this gap, we analyzed skin resident Tregs in a mouse model of IL-23 mediated psoriasiform dermatitis. Our results demonstrate that IL-23 drove the accumulation of Tregs; including a subpopulation that co-expressed RORγt and produced IL-17A. Genesis of this population was attenuated by a RORγt inverse agonist compound and clinically relevant therapeutics. In vitro, IL-23 drove the generation of CD4+ Foxp3+ RORγt+ IL-17A+ cells from Treg cells. Collectively, our data shows that IL-23 drives Treg plasticity by inducing a population of CD4+ Foxp3+ RORγt+ IL-17A+ cells that could play a role in the disease pathogenesis. Through this work, we define an in vitro system and a pre-clinical in vivo mouse model that can be used to further study Treg homeostasis and plasticity in the context of psoriasis.- Published
- 2019
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7. Inhibition of Interleukin-23-Mediated Inflammation with a Novel Small Molecule Inverse Agonist of ROR γ t.
- Author
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Gauld SB, Jacquet S, Gauvin D, Wallace C, Wang Y, McCarthy R, Goess C, Leys L, Huang S, Su Z, Edelmayer R, Wetter J, Salte K, McGaraughty SP, Argiriadi MA, Honore P, Luccarini JM, Bressac D, Desino K, Breinlinger E, Cusack K, Potin D, Kort ME, and Masson PJ
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, COS Cells, Cells, Cultured, Chlorocebus aethiops, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Piperidines therapeutic use, Anti-Inflammatory Agents therapeutic use, Arthritis drug therapy, Interleukin-23 metabolism, Nuclear Receptor Subfamily 1, Group F, Member 3 agonists, Piperidines pharmacology, Psoriasis drug therapy
- Abstract
Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of retinoid acid-related orphan receptor (ROR) γ t and its efficacy in preclinical models of psoriasis and arthritis. 1-(2,4-Dichloro-3-((1,4-dimethyl-6-(trifluoromethyl)-1H-indol-2-yl)methyl)benzoyl)piperidine-4-carboxylic acid (A-9758) was optimized from material identified from a high-throughput screening campaign. A-9758 is selective for ROR γ t and exhibits robust potency against IL-17A release both in vitro and in vivo. In vivo, we also show that IL-23 is sufficient to drive the accumulation of ROR γ t
+ cells, and inhibition of ROR γ t significantly attenuates IL-23-driven psoriasiform dermatitis. Therapeutic treatment with A-9758 (i.e., delivered during active disease) was also effective in blocking skin and joint inflammation. Finally, A-9758 exhibited efficacy in an ex vivo human whole blood assay, suggesting small molecule inverse agonists of ROR γ t could be efficacious in human IL-17-related diseases. SIGNIFICANCE STATEMENT: Using a novel small molecule inverse agonist, and preclinical assays, we show that ROR γ t is a viable target for the inhibition of ROR γ t/Th17-driven diseases such as psoriasis. Preclinical models of psoriasis show that inhibition of ROR γ t blocks both the accumulation and effector function of IL-17-producing T cells., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2019
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8. Discovery of novel quinoline sulphonamide derivatives as potent, selective and orally active RORγ inverse agonists.
- Author
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Amaudrut J, Argiriadi MA, Barth M, Breinlinger EC, Bressac D, Broqua P, Calderwood DJ, Chatar M, Cusack KP, Gauld SB, Jacquet S, Kamath RV, Kort ME, Lepais V, Luccarini JM, Masson P, Montalbetti C, Mounier L, Potin D, Poupardin O, Rouaud S, Spitzer L, and Wallace CD
- Subjects
- Animals, Disease Models, Animal, Humans, Mice, Drug Inverse Agonism, Nuclear Receptor Subfamily 1, Group F, Member 3 chemistry, Quinolines chemistry
- Abstract
A high-throughput screen against Inventiva's compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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9. Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists.
- Author
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Gomtsyan A, Schmidt RG, Bayburt EK, Gfesser GA, Voight EA, Daanen JF, Schmidt DL, Cowart MD, Liu H, Altenbach RJ, Kort ME, Clapham B, Cox PB, Shrestha A, Henry R, Whittern DN, Reilly RM, Puttfarcken PS, Brederson JD, Song P, Li B, Huang SM, McDonald HA, Neelands TR, McGaraughty SP, Gauvin DM, Joshi SK, Banfor PN, Segreti JA, Shebley M, Faltynek CR, Dart MJ, and Kym PR
- Subjects
- Calcium metabolism, Cyclobutanes chemistry, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Molecular Conformation, Pyridines chemistry, Structure-Activity Relationship, TRPV Cation Channels metabolism, Cyclobutanes chemical synthesis, Cyclobutanes pharmacology, Pyridines chemical synthesis, Pyridines pharmacology, TRPV Cation Channels antagonists & inhibitors
- Abstract
Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.
- Published
- 2016
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10. Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain.
- Author
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Frost JM, DeGoey DA, Shi L, Gum RJ, Fricano MM, Lundgaard GL, El-Kouhen OF, Hsieh GC, Neelands T, Matulenko MA, Daanen JF, Pai M, Ghoreishi-Haack N, Zhan C, Zhang XF, and Kort ME
- Subjects
- Analgesics chemistry, Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Electrophysiology, Evoked Potentials, Imidazolidines chemistry, Indazoles chemistry, Iodoacetic Acid toxicity, Molecular Structure, NAV1.7 Voltage-Gated Sodium Channel metabolism, Osteoarthritis chemically induced, Osteoarthritis metabolism, Pain metabolism, Pain pathology, Pain Measurement, Pyrroles chemistry, Rats, Sodium Channel Blockers chemistry, Structure-Activity Relationship, Analgesics pharmacology, Imidazolidines pharmacology, Indazoles pharmacology, NAV1.7 Voltage-Gated Sodium Channel chemistry, Osteoarthritis drug therapy, Pain drug therapy, Pyrroles pharmacology, Sodium Channel Blockers pharmacology
- Abstract
The genetic validation for the role of the Nav1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog 7 which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, 27 and 48, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both 27 and 48 demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of 48 showed a shift to a lower EC50 over 7 days.
- Published
- 2016
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11. TRPV1 ligands with hyperthermic, hypothermic and no temperature effects in rats.
- Author
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Gomtsyan A, McDonald HA, Schmidt RG, Daanen JF, Voight EA, Segreti JA, Puttfarcken PS, Reilly RM, Kort ME, Dart MJ, and Kym PR
- Abstract
Transient receptor potential vanilloid 1 (TRPV1) is a multifunctional ion channel playing important roles in a numerous biological processes including the regulation of body temperature. Within distinct and tight chemical space of chromanyl ureas TRPV1 ligands were identified that exhibit distinctive pharmacology and a spectrum of thermoregulatory effects ranging from hypothermia to hyperthermia. The ability to manipulate these effects by subtle structural modifications of chromanyl ureas may serve as a productive approach in TRPV1 drug discovery programs addressing either side effect or desired target profiles of the compounds. Because chromanyl ureas in the TRPV1 context are generally antagonists, we verified observed partial agonist effects of a subset of compounds within that chemotype by comparing the in vitro profile of Compound 3 with known partial agonist 5'-I-RTX.
- Published
- 2015
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12. Discovery of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442): a temperature-neutral transient receptor potential vanilloid-1 (TRPV1) antagonist with analgesic efficacy.
- Author
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Voight EA, Gomtsyan AR, Daanen JF, Perner RJ, Schmidt RG, Bayburt EK, DiDomenico S, McDonald HA, Puttfarcken PS, Chen J, Neelands TR, Bianchi BR, Han P, Reilly RM, Franklin PH, Segreti JA, Nelson RA, Su Z, King AJ, Polakowski JS, Baker SJ, Gauvin DM, Lewis LR, Mikusa JP, Joshi SK, Faltynek CR, Kym PR, and Kort ME
- Subjects
- Analgesics pharmacokinetics, Analgesics pharmacology, Animals, Area Under Curve, Body Temperature physiology, Dogs, Dose-Response Relationship, Drug, Drug Discovery, HEK293 Cells, Humans, Isoquinolines chemistry, Isoquinolines pharmacokinetics, Isoquinolines pharmacology, Metabolic Clearance Rate, Models, Chemical, Molecular Structure, Rats, Structure-Activity Relationship, TRPV Cation Channels chemistry, TRPV Cation Channels metabolism, Urea analogs & derivatives, Urea pharmacokinetics, Urea pharmacology, Analgesics chemistry, Body Temperature drug effects, TRPV Cation Channels antagonists & inhibitors, Urea chemistry
- Abstract
The synthesis and characterization of a series of selective, orally bioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described. Whereas first-generation antagonists that inhibit all modes of TRPV1 activation can elicit hyperthermia, the compounds disclosed herein do not elevate core body temperature in preclinical models and only partially block acid activation of TRPV1. Advancing the SAR of this series led to the eventual identification of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442, 52), an analogue that possesses excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents.
- Published
- 2014
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13. Transient receptor potential channel ankyrin-1 is not a cold sensor for autonomic thermoregulation in rodents.
- Author
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de Oliveira C, Garami A, Lehto SG, Pakai E, Tekus V, Pohoczky K, Youngblood BD, Wang W, Kort ME, Kym PR, Pinter E, Gavva NR, and Romanovsky AA
- Subjects
- Animals, Body Temperature Regulation drug effects, CHO Cells, Cold Temperature, Cricetulus, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, HSP90 Heat-Shock Proteins, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Intracellular Signaling Peptides and Proteins genetics, Male, Mice, Mice, Transgenic, Oximes blood, Oximes pharmacology, Pain chemically induced, Pain drug therapy, Rats, Rats, Sprague-Dawley, Rats, Wistar, Skin Temperature drug effects, TRPM Cation Channels antagonists & inhibitors, Thermosensing drug effects, Autonomic Nervous System physiology, Body Temperature Regulation genetics, Intracellular Signaling Peptides and Proteins physiology, Thermosensing genetics
- Abstract
The rodent transient receptor potential ankyrin-1 (TRPA1) channel has been hypothesized to serve as a temperature sensor for thermoregulation in the cold. We tested this hypothesis by using deletion of the Trpa1 gene in mice and pharmacological blockade of the TRPA1 channel in rats. In both Trpa1(-/-) and Trpa1(+/+) mice, severe cold exposure (8°C) resulted in decreases of skin and deep body temperatures to ∼8°C and 13°C, respectively, both temperatures being below the reported 17°C threshold temperature for TRPA1 activation. Under these conditions, Trpa1(-/-) mice had the same dynamics of body temperature as Trpa1(+/+) mice and showed no weakness in the tail skin vasoconstriction response or thermogenic response to cold. In rats, the effects of pharmacological blockade were studied by using two chemically unrelated TRPA1 antagonists: the highly potent and selective compound A967079, which had been characterized earlier, and the relatively new compound 43 ((4R)-1,2,3,4-tetrahydro-4-[3-(3-methoxypropoxy)phenyl]-2-thioxo-5H-indeno[1,2-d]pyrimidin-5-one), which we further characterized in the present study and found to be highly potent (IC50 against cold of ∼8 nm) and selective. Intragastric administration of either antagonist at 30 mg/kg before severe (3°C) cold exposure did not affect the thermoregulatory responses (deep body and tail skin temperatures) of rats, even though plasma concentrations of both antagonists well exceeded their IC50 value at the end of the experiment. In the same experimental setup, blocking the melastatin-8 (TRPM8) channel with AMG2850 (30 mg/kg) attenuated cold-defense mechanisms and led to hypothermia. We conclude that TRPA1 channels do not drive autonomic thermoregulatory responses to cold in rodents.
- Published
- 2014
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14. Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature.
- Author
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Reilly RM, McDonald HA, Puttfarcken PS, Joshi SK, Lewis L, Pai M, Franklin PH, Segreti JA, Neelands TR, Han P, Chen J, Mantyh PW, Ghilardi JR, Turner TM, Voight EA, Daanen JF, Schmidt RG, Gomtsyan A, Kort ME, Faltynek CR, and Kym PR
- Subjects
- Analgesics pharmacology, Animals, Calcitonin Gene-Related Peptide metabolism, Calcium metabolism, Capsaicin pharmacology, Cell Line, Transformed, Fever drug therapy, Fever physiopathology, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C3H, Neurons drug effects, Neurons metabolism, Pain drug therapy, Pain metabolism, Pain physiopathology, Protons, Rats, Rats, Sprague-Dawley, Recombinant Proteins antagonists & inhibitors, Recombinant Proteins metabolism, TRPV Cation Channels metabolism, Body Temperature drug effects, TRPV Cation Channels antagonists & inhibitors
- Abstract
The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (≥ 43°C), acidic pH (< 6), and endogenous lipids including N-arachidonoyl dopamine (NADA). Antagonists that block all modes of TRPV1 activation elicit hyperthermia. To identify efficacious TRPV1 antagonists that do not affect temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca(2+) flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain.
- Published
- 2012
- Full Text
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15. Capsaicin-induced inhibition of platelet aggregation is not mediated by transient receptor potential vanilloid type 1.
- Author
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Mittelstadt SW, Nelson RA, Daanen JF, King AJ, Kort ME, Kym PR, Lubbers NL, Cox BF, and Lynch JJ 3rd
- Subjects
- Animals, Dogs, Male, TRPV Cation Channels agonists, TRPV Cation Channels antagonists & inhibitors, Capsaicin pharmacology, Platelet Aggregation drug effects, TRPV Cation Channels metabolism
- Abstract
Capsaicin is an agonist of transient receptor potential vanilloid type 1 (TRPV1), in which it can act as a neuronal stimulant and result in nociception. Capsaicin also affects a variety of nonneuronal tissues, in which its mechanisms of action are less certain. The present study investigated whether the inhibitory effects of capsaicin on platelet aggregation are mediated via TRPV1. Venous whole blood obtained from beagle dogs (n = 6) was preincubated with capsaicin and/or the potent and selective competitive TRPV1 antagonist, A-993610 and then exposed to collagen (2 μg/ml). An aggregometer was used to quantify the platelet response. Capsaicin exposure inhibited collagen-induced platelet aggregation in a concentration-dependent manner, with significant effects at 10 and 30 μg capsaicin per millilitre. A-993610 alone (0.1-1.0 μg/ml) had no effects on collagen-induced platelet aggregation, nor did it have any effects on capsaicin's ability to inhibit platelet aggregation. The current results agree with previous findings that capsaicin can inhibit platelet aggregation. In addition, the present study demonstrates that capsaicin's inhibitory effect on collagen-induced canine platelet aggregation is not mediated by TRPV1.
- Published
- 2012
- Full Text
- View/download PDF
16. TRPV1 antagonists: clinical setbacks and prospects for future development.
- Author
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Kort ME and Kym PR
- Subjects
- Analgesics, Non-Narcotic chemistry, Analgesics, Non-Narcotic pharmacology, Analgesics, Non-Narcotic therapeutic use, Benzothiazoles therapeutic use, Body Temperature Regulation drug effects, Humans, Pyrimidines therapeutic use, Urea pharmacology, Benzimidazoles pharmacology, Benzothiazoles pharmacology, Indazoles pharmacology, Pyridines pharmacology, Pyrimidines pharmacology, Pyrrolidines pharmacology, TRPV Cation Channels antagonists & inhibitors, Urea analogs & derivatives
- Published
- 2012
- Full Text
- View/download PDF
17. Synthesis of oxazolo[4,5-c]quinoline TRPV1 antagonists.
- Author
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Voight EA, Daanen JF, and Kort ME
- Subjects
- Capsaicin chemistry, Crystallography, X-Ray, Heterocyclic Compounds chemistry, Magnetic Resonance Spectroscopy, Molecular Structure, Oxazoles chemistry, Quinolines chemistry, Structure-Activity Relationship, TRPV Cation Channels chemistry, Thiourea chemistry, Heterocyclic Compounds chemical synthesis, Oxazoles chemical synthesis, Quinolines chemical synthesis, TRPV Cation Channels antagonists & inhibitors, Thiourea chemical synthesis
- Abstract
An efficient synthesis of 2-amino-oxazolo[4,5-c]quinoline TRPV1 antagonists is described via a thiourea formation/carbodiimide cyclization sequence. Synthetic route optimization eliminates intermediate isolations and facilitates the rapid preparation of a series of novel pentacyclic TRPV1 antagonists. From this series, compound (S)-4 was identified as a potent and selective ligand for the TRPV1 ion channel.
- Published
- 2010
- Full Text
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18. Subtype-selective Na(v)1.8 sodium channel blockers: identification of potent, orally active nicotinamide derivatives.
- Author
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Kort ME, Atkinson RN, Thomas JB, Drizin I, Johnson MS, Secrest MA, Gregg RJ, Scanio MJ, Shi L, Hakeem AH, Matulenko MA, Chapman ML, Krambis MJ, Liu D, Shieh CC, Zhang X, Simler G, Mikusa JP, Zhong C, Joshi S, Honore P, Roeloffs R, Werness S, Antonio B, Marsh KC, Faltynek CR, Krafte DS, Jarvis MF, and Marron BE
- Subjects
- Administration, Oral, Animals, Biological Availability, Niacinamide chemistry, Niacinamide pharmacokinetics, Rats, Sodium Channel Blockers administration & dosage, Sodium Channel Blockers chemistry, Sodium Channel Blockers pharmacokinetics, Structure-Activity Relationship, Niacinamide pharmacology, Sodium Channel Blockers pharmacology
- Abstract
A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Na(v)1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic pain., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
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19. Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Na(v)1.8 sodium channel with efficacy in a model of neuropathic pain.
- Author
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Scanio MJ, Shi L, Drizin I, Gregg RJ, Atkinson RN, Thomas JB, Johnson MS, Chapman ML, Liu D, Krambis MJ, Liu Y, Shieh CC, Zhang X, Simler GH, Joshi S, Honore P, Marsh KC, Knox A, Werness S, Antonio B, Krafte DS, Jarvis MF, Faltynek CR, Marron BE, and Kort ME
- Subjects
- Administration, Oral, Animals, Disease Models, Animal, Drug Evaluation, Preclinical, Ganglia, Spinal cytology, Humans, Microsomes metabolism, NAV1.8 Voltage-Gated Sodium Channel, Neurons metabolism, Pyrazines pharmacokinetics, Pyrazines therapeutic use, Rats, Sodium Channel Blockers pharmacokinetics, Sodium Channel Blockers therapeutic use, Sodium Channels metabolism, Structure-Activity Relationship, Neuralgia drug therapy, Pyrazines chemistry, Sodium Channel Blockers chemistry, Sodium Channels chemistry
- Abstract
Na(v)1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons. It has been implicated in the pathophysiology of inflammatory and neuropathic pain, and we envisioned that selective blockade of Na(v)1.8 would be analgesic, while reducing adverse events typically associated with non-selective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 6-aryl-2-pyrazinecarboxamides, which are potent blockers of the human Na(v)1.8 channel and also block TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons. Selected derivatives display selectivity versus human Na(v)1.2. We further demonstrate that an example from this series is orally bioavailable and produces antinociceptive activity in vivo in a rodent model of neuropathic pain following oral administration., (Copyright © 2010. Published by Elsevier Ltd.)
- Published
- 2010
- Full Text
- View/download PDF
20. Transient receptor potential vanilloid-1 antagonists: a survey of recent patent literature.
- Author
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Voight EA and Kort ME
- Subjects
- Analgesics pharmacology, Animals, Chronic Disease, Clinical Trials as Topic, Humans, Pain physiopathology, Patents as Topic, Drug Design, Pain drug therapy, TRPV Cation Channels antagonists & inhibitors
- Abstract
Importance of the Field: Transient receptor potential vanilloid-1 (TRPV1, vanilloid receptor-1) is a nonspecific cation channel that can be activated by multiple endogenous stimuli and by capsaicin, the active ingredient in chili peppers. TRPV1 is expressed predominantly on sensory neurons where it is proposed to serve as a key nodal point in pain transmission pathways. Pharmacological blockade of TRPV1 represents a compelling strategy for the treatment of a variety of disease states, particularly those requiring chronic pain management. AREA COVERED IN THE REVIEW: This review summarizes patent literature and progress in defining the utility of small molecule TRPV1 antagonists during 2008-2009., What the Reader Will Gain: Representative compounds and key characterization data comprising multiple chemical series are highlighted., Take Home Message: The continued profusion of reports, in both the primary and patent literature, attests to the sustained interest in the TRPV1 class of therapeutics. Although a number of compounds have now been brought forward for human clinical trials, the therapeutic utility of TRPV1 antagonists is yet to be validated unequivocally.
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- 2010
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21. A-887826 is a structurally novel, potent and voltage-dependent Na(v)1.8 sodium channel blocker that attenuates neuropathic tactile allodynia in rats.
- Author
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Zhang XF, Shieh CC, Chapman ML, Matulenko MA, Hakeem AH, Atkinson RN, Kort ME, Marron BE, Joshi S, Honore P, Faltynek CR, Krafte DS, and Jarvis MF
- Subjects
- Animals, Biophysics, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Electric Stimulation methods, Ganglia, Spinal cytology, Humans, Hyperalgesia etiology, Male, Membrane Potentials drug effects, Morpholines chemistry, Morpholines pharmacology, Morpholines therapeutic use, NAV1.8 Voltage-Gated Sodium Channel, Neuralgia complications, Neuralgia etiology, Niacinamide analogs & derivatives, Niacinamide chemistry, Niacinamide pharmacology, Niacinamide therapeutic use, Patch-Clamp Techniques methods, Rats, Rats, Sprague-Dawley, Sensory Receptor Cells drug effects, Sodium Channel Blockers chemistry, Sodium Channels drug effects, Spinal Cord Injuries complications, Tetrodotoxin pharmacology, Transfection methods, Hyperalgesia drug therapy, Pain Threshold drug effects, Sodium Channel Blockers pharmacology, Sodium Channel Blockers therapeutic use, Sodium Channels metabolism
- Abstract
Activation of sodium channels is essential to action potential generation and propagation. Recent genetic and pharmacological evidence indicates that activation of Na(v)1.8 channels contributes to chronic pain. Herein, we describe the identification of a novel series of structurally related pyridine derivatives as potent Na(v)1.8 channel blockers. A-887826 exemplifies this series and potently (IC(50)=11nM) blocked recombinant human Na(v)1.8 channels. A-887826 was approximately 3 fold less potent to block Na(v)1.2, approximately 10 fold less potent to block tetrodotoxin-sensitive sodium (TTX-S Na(+)) currents and was >30 fold less potent to block Na(V)1.5 channels. A-887826 potently blocked tetrodotoxin-resistant sodium (TTX-R Na(+)) currents (IC(50)=8nM) from small diameter rat dorsal root ganglion (DRG) neurons in a voltage-dependent fashion. A-887826 effectively suppressed evoked action potential firing when DRG neurons were held at depolarized potentials and reversibly suppressed spontaneous firing in small diameter DRG neurons from complete Freund's adjuvant inflamed rats. Following oral administration, A-887826 significantly attenuated tactile allodynia in a rat neuropathic pain model. Further characterization of TTX-R current block in rat DRG neurons demonstrated that A-887826 (100nM) shifted the mid-point of voltage-dependent inactivation of TTX-R currents by approximately 4mV without affecting voltage-dependent activation and did not exhibit frequency-dependent inhibition. The present data demonstrate that A-887826 is a structurally novel and potent Na(v)1.8 blocker that inhibits rat DRG TTX-R currents in a voltage-, but not frequency-dependent fashion. The ability of this structurally novel Na(v)1.8 blocker to effectively reduce tactile allodynia in neuropathic rats further supports the role of Na(v)1.8 sodium channels in pathological pain states., (Copyright 2010 Elsevier Ltd. All rights reserved.)
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- 2010
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22. Synthesis and biological evaluation of 5-substituted and 4,5-disubstituted-2-arylamino oxazole TRPV1 antagonists.
- Author
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Perner RJ, Koenig JR, Didomenico S, Gomtsyan A, Schmidt RG, Lee CH, Hsu MC, McDonald HA, Gauvin DM, Joshi S, Turner TM, Reilly RM, Kym PR, and Kort ME
- Subjects
- Cell Line, Crystallography, X-Ray, Humans, Molecular Conformation, Naphthols chemistry, Naphthols pharmacokinetics, Oxazoles chemical synthesis, Oxazoles pharmacokinetics, TRPV Cation Channels metabolism, Naphthols chemical synthesis, Oxazoles chemistry, TRPV Cation Channels antagonists & inhibitors
- Abstract
The synthesis and structure-activity relationships of a series of 5-monosubstituted and 4,5-disubstituted 2-arylaminooxazoles as novel antagonists of the transient receptor potential vanilloid 1 (TRPV1) receptor are described. The 7-hydroxy group of the tetrahydronaphthyl moiety on the 2-amino substituent of the oxazole ring was important for obtaining excellent in vitro potency at the human TRPV1 receptor, while a variety of alkyl and phenyl substituents at the 4- and 5-positions of the oxazole ring were well tolerated and yielded potent TRPV1 antagonists. Despite excellent in vitro potency, the 5-monosubstituted compounds suffered from poor pharmacokinetics. It was found that 4,5-disubstitution on the oxazole ring was critical to the improvement of the overall pharmacokinetic profile of these analogues, which led to the discovery of compound (R)-27, a novel TRPV1 antagonist with good oral activity in preclinical animal models of pain., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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23. TRPA1 modulation of spontaneous and mechanically evoked firing of spinal neurons in uninjured, osteoarthritic, and inflamed rats.
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McGaraughty S, Chu KL, Perner RJ, Didomenico S, Kort ME, and Kym PR
- Subjects
- Action Potentials drug effects, Animals, Ankyrins, Calcium Channels drug effects, Disease Models, Animal, Inflammation complications, Inflammation physiopathology, Mechanoreceptors drug effects, Mechanoreceptors physiology, Osteoarthritis complications, Osteoarthritis physiopathology, Pain drug therapy, Pain physiopathology, Pain Measurement drug effects, Pain Threshold drug effects, Pain Threshold physiology, Physical Stimulation, Posterior Horn Cells drug effects, Rats, Spinal Cord drug effects, Synaptic Transmission drug effects, Synaptic Transmission physiology, TRPA1 Cation Channel, TRPC Cation Channels, Action Potentials physiology, Calcium Channels metabolism, Pain metabolism, Posterior Horn Cells metabolism, Spinal Cord metabolism
- Abstract
Background: There is growing evidence supporting a role for TRPA1 receptors in the neurotransmission of peripheral mechanical stimulation. In order to enhance understanding of TRPA1 contributions to mechanotransmission, we examined the effects a selective TRPA1 receptor antagonist, A-967079, on spinal neuronal activity following peripheral mechanical stimulation in uninjured, CFA-inflamed, and osteoarthritc (OA) rats., Results: Systemic injection of A-967079 (30 micromol/kg, i.v.) decreased the responses of wide dynamic range (WDR), and nociceptive specific (NS) neurons following noxious pinch stimulation of the ipsilateral hind paw in uninjured and CFA-inflamed rats. Similarly, A-967079 reduced the responses of WDR neurons to high-intensity mechanical stimulation (300 g von Frey hair) of the knee joint in both OA and OA-sham rats. WDR neuronal responses to low-intensity mechanical stimulation (10 g von Frey hair) were also reduced by A-967079 administration to CFA-inflamed rats, but no effect was observed in uninjured rats. Additionally, the spontaneous activity of WDR neurons was decreased after A-967079 injection in CFA-inflamed rats but was unaltered in uninjured, OA, and OA-sham animals., Conclusions: Blockade of TRPA1 receptors disrupts transmission of high-intensity mechanical stimulation to the spinal cord in both uninjured and injured rats indicating that TRPA1 receptors have an important role in noxious mechanosensation in both normal and pathological conditions. TRPA1 receptors also contribute to the transmission of low-intensity mechanical stimulation, and to the modulation of spontaneous WDR firing, but only after an inflammatory injury.
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- 2010
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24. Analgesic potential of TRPV1 antagonists.
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Kym PR, Kort ME, and Hutchins CW
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- Animals, Models, Molecular, Structure-Activity Relationship, TRPV Cation Channels chemistry, TRPV Cation Channels physiology, Temperature, Urea pharmacology, Analgesics pharmacology, Benzothiazoles pharmacology, Indazoles pharmacology, Pyrimidines pharmacology, Pyrrolidines pharmacology, TRPV Cation Channels antagonists & inhibitors, Urea analogs & derivatives
- Abstract
The discovery of TRPV1 antagonists as a new class of analgesic agents for the treatment of chronic pathological pain has been pursued aggressively across the pharmaceutical industry. This effort has led to the identification of several TRPV1 antagonists that have entered clinical trials, including ABT-102 (Abbott), SB-705498 (GSK), AMG-517 (Amgen), MK2295 (Merck/Neurogen), and GRC-6211 (Lilly/Glenmark). Using the published structures for ABT-102, SB-705498, AMG-517, and lead compounds representing six additional TRPV1 antagonist chemotypes, a pharmacophore model that describes the common structural features found in potent TRPV1 antagonists was established. The TRPV1 antagonist pharmacophore fits within the pore region of a TRPV1 receptor homology model, with critical hydrogen bond interactions proposed between the TRPV1 antagonist pharmacophore and Tyr 667 on helix six. In spite of the putative common binding site for all TRPV1 antagonists included in this particular TRPV1 pharmacophore, these ligands have demonstrated that they can still offer distinct pharmacological profiles, likely due to differences in their pharmacokinetic profiles. This is highlighted by differences in temperature elevation observed when comparing the clinical candidates ABT-102 and AMG-517.
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- 2009
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25. Repeated dosing of ABT-102, a potent and selective TRPV1 antagonist, enhances TRPV1-mediated analgesic activity in rodents, but attenuates antagonist-induced hyperthermia.
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Honore P, Chandran P, Hernandez G, Gauvin DM, Mikusa JP, Zhong C, Joshi SK, Ghilardi JR, Sevcik MA, Fryer RM, Segreti JA, Banfor PN, Marsh K, Neelands T, Bayburt E, Daanen JF, Gomtsyan A, Lee CH, Kort ME, Reilly RM, Surowy CS, Kym PR, Mantyh PW, Sullivan JP, Jarvis MF, and Faltynek CR
- Subjects
- Animals, Body Temperature drug effects, Bone Neoplasms complications, Calcium metabolism, Disease Models, Animal, Drug Interactions, Fever chemically induced, Inflammation complications, Male, Mice, Mice, Inbred C3H, Motor Activity drug effects, Osteoarthritis complications, Pain etiology, Pain Measurement, Rats, Rats, Sprague-Dawley, TRPV Cation Channels antagonists & inhibitors, Urea administration & dosage, Analgesics administration & dosage, Fever drug therapy, Indazoles administration & dosage, Pain drug therapy, Pain Threshold drug effects, TRPV Cation Channels metabolism, Urea analogs & derivatives
- Abstract
Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated ion channel that functions as an integrator of multiple pain stimuli including heat, acid, capsaicin and a variety of putative endogenous lipid ligands. TRPV1 antagonists have been shown to decrease inflammatory pain in animal models and to produce limited hyperthermia at analgesic doses. Here, we report that ABT-102, which is a potent and selective TRPV1 antagonist, is effective in blocking nociception in rodent models of inflammatory, post-operative, osteoarthritic, and bone cancer pain. ABT-102 decreased both spontaneous pain behaviors and those evoked by thermal and mechanical stimuli in these models. Moreover, we have found that repeated administration of ABT-102 for 5-12 days increased its analgesic activity in models of post-operative, osteoarthritic, and bone cancer pain without an associated accumulation of ABT-102 concentration in plasma or brain. Similar effects were also observed with a structurally distinct TRPV1 antagonist, A-993610. Although a single dose of ABT-102 produced a self-limiting increase in core body temperature that remained in the normal range, the hyperthermic effects of ABT-102 effectively tolerated following twice-daily dosing for 2 days. Therefore, the present data demonstrate that, following repeated administration, the analgesic activity of TRPV1 receptor antagonists is enhanced, while the associated hyperthermic effects are attenuated. The analgesic efficacy of ABT-102 supports its advancement into clinical studies.
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- 2009
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26. Voltage-gated sodium channel blockers for the treatment of chronic pain.
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Matulenko MA, Scanio MJ, and Kort ME
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- Humans, Ion Channel Gating, Sodium Channel Blockers therapeutic use, Sodium Channels drug effects, Structure-Activity Relationship, Pain drug therapy, Sodium Channel Blockers pharmacology
- Abstract
The voltage-gated sodium channels are a family of proteins that control the flow of sodium ions across cell membranes. Considerable data support the hypothesis that hyperexcitability and spontaneous action potential firing in peripheral sensory neurons mediated by voltage-gated sodium channels contribute to the pathophysiology of chronic pain. Sodium channel blockers are, therefore, appealing entities for therapeutic intervention in painful human neuropathies. This review will focus on the latest advances in the development of small molecule sodium channel blockers and their application to the treatment of chronic pain.
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- 2009
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27. Discovery of potent furan piperazine sodium channel blockers for treatment of neuropathic pain.
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Drizin I, Gregg RJ, Scanio MJ, Shi L, Gross MF, Atkinson RN, Thomas JB, Johnson MS, Carroll WA, Marron BE, Chapman ML, Liu D, Krambis MJ, Shieh CC, Zhang X, Hernandez G, Gauvin DM, Mikusa JP, Zhu CZ, Joshi S, Honore P, Marsh KC, Roeloffs R, Werness S, Krafte DS, Jarvis MF, Faltynek CR, and Kort ME
- Subjects
- Analgesics, Non-Narcotic chemical synthesis, Animals, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Furans chemical synthesis, Humans, Male, Mice, Piperazines chemical synthesis, Rats, Rats, Sprague-Dawley, Sodium Channel Blockers chemical synthesis, Structure-Activity Relationship, Analgesics, Non-Narcotic chemistry, Analgesics, Non-Narcotic pharmacology, Furans chemistry, Furans pharmacology, Neuralgia drug therapy, Piperazines chemistry, Piperazines pharmacology, Sodium Channel Blockers chemistry, Sodium Channel Blockers pharmacology, Sodium Channels drug effects
- Abstract
The synthesis and pharmacological characterization of a novel furan-based class of voltage-gated sodium channel blockers is reported. Compounds were evaluated for their ability to block the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3) as well as the Na(v)1.2 and Na(v)1.5 subtypes. Benchmark compounds from this series possessed enhanced potency, oral bioavailability, and robust efficacy in a rodent model of neuropathic pain, together with improved CNS and cardiovascular safety profiles compared to the clinically used sodium channel blockers mexiletine and lamotrigine.
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- 2008
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28. Molecular determinants of species-specific activation or blockade of TRPA1 channels.
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Chen J, Zhang XF, Kort ME, Huth JR, Sun C, Miesbauer LJ, Cassar SC, Neelands T, Scott VE, Moreland RB, Reilly RM, Hajduk PJ, Kym PR, Hutchins CW, and Faltynek CR
- Subjects
- Animals, Ankyrins, Calcium Channels chemistry, Calcium Channels genetics, Cell Line, Humans, Ion Channel Gating physiology, Mutation, Nerve Tissue Proteins chemistry, Nerve Tissue Proteins genetics, Protein Structure, Tertiary, Rats, Species Specificity, TRPA1 Cation Channel, TRPC Cation Channels, Transient Receptor Potential Channels chemistry, Transient Receptor Potential Channels genetics, Benzamides pharmacology, Calcium Channels metabolism, Ion Channel Gating drug effects, Nerve Tissue Proteins antagonists & inhibitors, Nerve Tissue Proteins metabolism, Transient Receptor Potential Channels antagonists & inhibitors, Transient Receptor Potential Channels metabolism
- Abstract
TRPA1 is an excitatory, nonselective cation channel implicated in somatosensory function, pain, and neurogenic inflammation. Through covalent modification of cysteine and lysine residues, TRPA1 can be activated by electrophilic compounds, including active ingredients of pungent natural products (e.g., allyl isothiocyanate), environmental irritants (e.g., acrolein), and endogenous ligands (4-hydroxynonenal). However, how covalent modification leads to channel opening is not understood. Here, we report that electrophilic, thioaminal-containing compounds [e.g., CMP1 (4-methyl-N-[2,2,2-trichloro-1-(4-nitro-phenylsulfanyl)-ethyl]-benzamide)] covalently modify cysteine residues but produce striking species-specific effects [i.e., activation of rat TRPA1 (rTRPA1) and blockade of human TRPA1 (hTRPA1) activation by reactive and nonreactive agonists]. Through characterizing rTRPA1 and hTRPA1 chimeric channels and point mutations, we identified several residues in the upper portion of the S6 transmembrane domains as critical determinants of the opposite channel gating: Ala-946 and Met-949 of rTRPA1 determine channel activation, whereas equivalent residues of hTRPA1 (Ser-943 and Ile-946) determine channel block. Furthermore, side-chain replacements at these critical residues profoundly affect channel function. Therefore, our findings reveal a molecular basis of species-specific channel gating and provide novel insights into how TRPA1 respond to stimuli.
- Published
- 2008
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29. A selective Nav1.8 sodium channel blocker, A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], attenuates spinal neuronal activity in neuropathic rats.
- Author
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McGaraughty S, Chu KL, Scanio MJ, Kort ME, Faltynek CR, and Jarvis MF
- Subjects
- Aniline Compounds therapeutic use, Animals, Furans therapeutic use, Male, NAV1.8 Voltage-Gated Sodium Channel, Nerve Tissue Proteins antagonists & inhibitors, Pain prevention & control, Pain Measurement drug effects, Pain Measurement methods, Rats, Rats, Sprague-Dawley, Sodium Channel Blockers therapeutic use, Spinal Nerves drug effects, Synaptic Transmission drug effects, Aniline Compounds pharmacology, Furans pharmacology, Nerve Tissue Proteins physiology, Pain physiopathology, Sodium Channel Blockers pharmacology, Sodium Channels physiology, Spinal Nerves physiology, Synaptic Transmission physiology
- Abstract
We have recently reported that systemic delivery of A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], a selective Na(v)1.8 sodium channel blocker, reduces behavioral measures of chronic pain. In the current study, the effects of A-803467 on evoked and spontaneous firing of wide dynamic range (WDR) neurons were measured in uninjured and rats with spinal nerve ligations (SNLs). Administration of A-803467 (10-30 mg/kg i.v.) reduced mechanically evoked (10-g von Frey hair) and spontaneous WDR neuronal activity in SNL rats. In uninjured rats, A-803467 (20 mg/kg i.v.) transiently reduced evoked but not spontaneous firing of WDR neurons. The systemic effects of A-803467 in SNL rats were not altered by spinal transection or by systemic pretreatment with the transient receptor potential vanilloid type 1 (TRPV1) receptor agonist, resiniferatoxin, at doses that impair the function of TRPV1-expressing fibers. To determine sites of action, A-803467 was administered into spinal tissue, into the uninjured L4 dorsal root ganglion (DRG), or into the neuronal receptive field. Injections of A-803467 into the L4 DRG (30-100 nmol/1 mul) or into the hindpaw receptive field (300 nmol/50 mul) reduced evoked but not spontaneous WDR firing. In contrast, intraspinal (50-150 nmol/0.5 mul) injection of A-803467 decreased both evoked and spontaneous discharges of WDR neurons. Thus, Na(v)1.8 sodium channels on the cell bodies/axons within the L4 DRG as well as on peripheral and central terminals of primary afferent neurons regulate the inflow of low-intensity mechanical signals to spinal WDR neurons. However, Na(v)1.8 sodium channels on central terminals seem to be key to the modulation of spontaneous firing in SNL rats.
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- 2008
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30. Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain.
- Author
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Kort ME, Drizin I, Gregg RJ, Scanio MJ, Shi L, Gross MF, Atkinson RN, Johnson MS, Pacofsky GJ, Thomas JB, Carroll WA, Krambis MJ, Liu D, Shieh CC, Zhang X, Hernandez G, Mikusa JP, Zhong C, Joshi S, Honore P, Roeloffs R, Marsh KC, Murray BP, Liu J, Werness S, Faltynek CR, Krafte DS, Jarvis MF, Chapman ML, and Marron BE
- Subjects
- Amides chemistry, Amides pharmacology, Analgesics pharmacokinetics, Analgesics pharmacology, Animals, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cell Line, Cricetinae, Cricetulus, Furans chemistry, Furans pharmacokinetics, Furans pharmacology, Ganglia, Spinal cytology, Humans, In Vitro Techniques, Male, Mice, NAV1.8 Voltage-Gated Sodium Channel, Nerve Tissue Proteins physiology, Neurons drug effects, Neurons physiology, Pain drug therapy, Pain etiology, Patch-Clamp Techniques, Peripheral Nervous System Diseases drug therapy, Rats, Rats, Sprague-Dawley, Recombinant Proteins antagonists & inhibitors, Sodium Channel Blockers pharmacokinetics, Sodium Channel Blockers pharmacology, Structure-Activity Relationship, Amides chemical synthesis, Analgesics chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Furans chemical synthesis, Sodium Channel Blockers chemical synthesis, Sodium Channels physiology
- Abstract
Nav1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons and has been implicated in the pathophysiology of inflammatory and neuropathic pain. Recent studies using an Nav1.8 antisense oligonucleotide in an animal model of chronic pain indicated that selective blockade of Nav1.8 was analgesic and could provide effective analgesia with a reduction in the adverse events associated with nonselective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 5-substituted 2-furfuramides, which are potent, voltage-dependent blockers (IC50 < 10 nM) of the human Nav1.8 channel. Selected derivatives, such as 7 and 27, also blocked TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons with comparable potency and displayed >100-fold selectivity versus human sodium (Nav1.2, Nav1.5, Nav1.7) and human ether-a-go-go (hERG) channels. Following systemic administration, compounds 7 and 27 dose-dependently reduced neuropathic and inflammatory pain in experimental rodent models.
- Published
- 2008
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31. Structure-activity studies of novel cyanoguanidine ATP-sensitive potassium channel openers for the treatment of overactive bladder.
- Author
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Perez-Medrano A, Brune ME, Buckner SA, Coghlan MJ, Fey TA, Gopalakrishnan M, Gregg RJ, Kort ME, Scott VE, Sullivan JP, Whiteaker KL, and Carroll WA
- Subjects
- Administration, Oral, Animals, Benzamides pharmacokinetics, Benzamides pharmacology, Biological Availability, Crystallography, X-Ray, Dogs, Electric Stimulation, Female, Guanidines pharmacokinetics, Guanidines pharmacology, Humans, In Vitro Techniques, Ion Channel Gating, KATP Channels agonists, Muscle Relaxation, Muscle, Smooth drug effects, Muscle, Smooth physiology, Potassium Channels, Inwardly Rectifying agonists, Potassium Channels, Inwardly Rectifying physiology, Structure-Activity Relationship, Swine, Urinary Bladder cytology, Urinary Bladder drug effects, Urinary Bladder physiology, Urinary Bladder, Overactive physiopathology, Urodynamics, Benzamides chemical synthesis, Guanidines chemical synthesis, KATP Channels physiology, Urinary Bladder, Overactive drug therapy
- Abstract
A series of novel cyanoguanidine derivatives was designed and synthesized. Condensation of N-(1-benzotriazol-1-yl-2,2-dichloropropyl)-substituted benzamides with N-(substituted-pyridin-3-yl)-N'-cyanoguanidines furnished N-{2,2-dichloro-1-[N'-(substituted-pyridin-3-yl)-N''-cyanoguanidino]propyl}-substituted benzamide derivatives. These agents were glyburide-reversible potassium channel openers and hyperpolarized human bladder cells as assessed by the FLIPR membrane potential dye (KATP-FMP). These compounds were also potent full agonists in relaxing electrically stimulated pig bladder strips, an in vitro model of overactive bladder. The most active compound 9 was evaluated for in vivo efficacy and selectivity in a pig model of bladder instability. Preliminary pharmacokinetic studies in dog demonstrated excellent oral bioavailability and a t1/2 of 15 h. The synthesis, SAR studies, and biological properties of these agents are discussed.
- Published
- 2007
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32. P2X7-related modulation of pathological nociception in rats.
- Author
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McGaraughty S, Chu KL, Namovic MT, Donnelly-Roberts DL, Harris RR, Zhang XF, Shieh CC, Wismer CT, Zhu CZ, Gauvin DM, Fabiyi AC, Honore P, Gregg RJ, Kort ME, Nelson DW, Carroll WA, Marsh K, Faltynek CR, and Jarvis MF
- Subjects
- Action Potentials drug effects, Adenosine Triphosphate analogs & derivatives, Adenosine Triphosphate pharmacology, Analgesics pharmacology, Analgesics therapeutic use, Animals, Astrocytoma, Behavior, Animal drug effects, Cell Line, Tumor, Disease Models, Animal, Dose-Response Relationship, Drug, Ganglia, Spinal, Humans, Interleukin-1beta metabolism, Male, Mice, Mice, Inbred BALB C, Neurons, Pain Measurement methods, Purinergic P2 Receptor Agonists, Purinergic P2 Receptor Antagonists, Pyridines therapeutic use, Rats, Rats, Sprague-Dawley, Receptors, Purinergic P2X7, Sciatica drug therapy, Tetrazoles therapeutic use, Time Factors, Pyridines pharmacology, Receptors, Purinergic P2 physiology, Sciatica metabolism, Sciatica physiopathology, Tetrazoles pharmacology
- Abstract
Growing evidence supports a role for the immune system in the induction and maintenance of chronic pain. ATP is a key neurotransmitter in this process. Recent studies demonstrate that the glial ATP receptor, P2X7, contributes to the modulation of pathological pain. To further delineate the endogenous mechanisms that are involved in P2X7-related antinociception, we utilized a selective P2X7 receptor antagonist, A-438079, in a series of in vivo and in vitro experiments. Injection of A-438079 (10-300 micromol/kg, i.p.) was anti-allodynic in three different rat models of neuropathic pain and it attenuated formalin-induced nocifensive behaviors. Using in vivo electrophysiology, A-438079 (80 micromol/kg, i.v.) reduced noxious and innocuous evoked activity of different classes of spinal neurons (low threshold, nociceptive specific, wide dynamic range) in neuropathic rats. The effects of A-438079 on evoked firing were diminished or absent in sham rats. Spontaneous activity of all classes of spinal neurons was also significantly reduced by A-438079 in neuropathic but not sham rats. In vitro, A-438079 (1 microM) blocked agonist-induced (2,3-O-(4-benzoylbenzoyl)-ATP, 30 microM) current in non-neuronal cells taken from the vicinity of the dorsal root ganglia. Furthermore, A-438079 dose-dependently (0.3-3 microM) decreased the quantity of the cytokine, interleukin-1beta, released from peripheral macrophages. Thus, ATP, acting through the P2X7 receptor, exerts a wide-ranging influence on spinal neuronal activity following a chronic injury. Antagonism of the P2X7 receptor can in turn modulate central sensitization and produce antinociception in animal models of pathological pain. These effects are likely mediated through immuno-neural interactions that affect the release of endogenous cytokines.
- Published
- 2007
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33. Effects of substitution on 9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4- azacyclopenta[b]naphthalene-1,8-dione, a dihydropyridine ATP-sensitive potassium channel opener.
- Author
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Altenbach RJ, Brune ME, Buckner SA, Coghlan MJ, Daza AV, Fabiyi A, Gopalakrishnan M, Henry RF, Khilevich A, Kort ME, Milicic I, Scott VE, Smith JC, Whiteaker KL, and Carroll WA
- Subjects
- Animals, Aza Compounds chemistry, Aza Compounds pharmacology, Cell Line, Crystallography, X-Ray, Electric Stimulation, Heterocyclic Compounds, 3-Ring chemistry, Heterocyclic Compounds, 3-Ring pharmacology, In Vitro Techniques, Ion Channel Gating, Mice, Muscle Contraction, Muscle, Smooth drug effects, Muscle, Smooth physiology, Naphthalenes chemistry, Naphthalenes pharmacology, Stereoisomerism, Structure-Activity Relationship, Swine, Urinary Bladder drug effects, Urinary Bladder physiology, Adenosine Triphosphate physiology, Aza Compounds chemical synthesis, Dihydropyridines chemistry, Heterocyclic Compounds, 3-Ring chemical synthesis, Naphthalenes chemical synthesis, Potassium Channels, Inwardly Rectifying drug effects
- Abstract
Structure-activity relationships were investigated on the tricyclic dihydropyridine (DHP) KATP openers 9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (6) and 10-(3-bromo-4-fluorophenyl)-9,10-dihydro-1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (65). Substitution off the core of the DHP, absolute stereochemistry, and aromatic substitution were evaluated for KATP channel activity using Ltk- cells stably transfected with the Kir6.2/SUR2B exon 17- splice variant and in an electrically stimulated pig bladder strip assay. A select group of compounds was evaluated for in vitro inhibition of spontaneous bladder contractions. Several compounds were found to have the unique characteristic of partial efficacy in both the cell-based and electrically stimulated bladder strip assays but full efficacy in inhibiting spontaneous bladder strip contractions. For compound 23b, this profile was mirrored in vivo where it was fully efficacious in inhibiting spontaneous myogenic bladder contractions but only partially able to reduce neurogenically mediated reflex bladder contractions.
- Published
- 2006
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34. Structure-activity relationship studies on a series of novel, substituted 1-benzyl-5-phenyltetrazole P2X7 antagonists.
- Author
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Nelson DW, Gregg RJ, Kort ME, Perez-Medrano A, Voight EA, Wang Y, Grayson G, Namovic MT, Donnelly-Roberts DL, Niforatos W, Honore P, Jarvis MF, Faltynek CR, and Carroll WA
- Subjects
- Analgesics chemistry, Analgesics pharmacology, Animals, Cell Line, Humans, Interleukin-1 antagonists & inhibitors, Interleukin-1 metabolism, Ligation, Motor Activity drug effects, Pain drug therapy, Pain etiology, Patch-Clamp Techniques, Peripheral Nervous System Diseases complications, Physical Stimulation, Pyridines chemistry, Pyridines pharmacology, Rats, Receptors, Purinergic P2 physiology, Receptors, Purinergic P2X7, Spinal Nerves, Stereoisomerism, Structure-Activity Relationship, Tetrazoles chemistry, Tetrazoles pharmacology, Touch, Analgesics chemical synthesis, Purinergic P2 Receptor Antagonists, Pyridines chemical synthesis, Tetrazoles chemical synthesis
- Abstract
1-Benzyl-5-aryltetrazoles were discovered to be novel antagonists for the P2X(7) receptor. Structure-activity relationship (SAR) studies were conducted around both the benzyl and phenyl moieties. In addition, the importance of the regiochemical substitution on the tetrazole was examined. Compounds were evaluated for activity to inhibit calcium flux in both human and rat recombinant P2X(7) cell lines using fluorometric imaging plate reader technology. Analogues were also assayed for their ability to inhibit IL-1beta release and to inhibit P2X(7)-mediated pore formation in human THP-1 cells. Compound 15d was advanced to efficacy studies in a model of neuropathic pain where significant reversal of mechanical allodynia was observed at doses that did not affect motor coordination.
- Published
- 2006
- Full Text
- View/download PDF
35. Synthesis and structure-activity relationships of a novel series of 2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide K(ATP) channel openers: discovery of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9- hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a potent K(ATP) opener that selectively inhibits spontaneous bladder contractions.
- Author
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Carroll WA, Altenbach RJ, Bai H, Brioni JD, Brune ME, Buckner SA, Cassidy C, Chen Y, Coghlan MJ, Daza AV, Drizin I, Fey TA, Fitzgerald M, Gopalakrishnan M, Gregg RJ, Henry RF, Holladay MW, King LL, Kort ME, Kym PR, Milicic I, Tang R, Turner SC, Whiteaker KL, Yi L, Zhang H, and Sullivan JP
- Subjects
- Animals, Cyclic S-Oxides chemistry, Cyclic S-Oxides pharmacology, Electric Stimulation, Guinea Pigs, Hemodynamics drug effects, In Vitro Techniques, Membrane Potentials, Muscle Contraction drug effects, Muscle, Smooth cytology, Muscle, Smooth drug effects, Muscle, Smooth physiology, Quinolones chemistry, Quinolones pharmacology, Stereoisomerism, Structure-Activity Relationship, Swine, Urinary Bladder cytology, Urinary Bladder physiology, Urodynamics drug effects, Adenosine Triphosphate physiology, Cyclic S-Oxides chemical synthesis, Potassium Channels drug effects, Quinolones chemical synthesis, Urinary Bladder drug effects
- Abstract
Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing K(ATP) openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective K(ATP) channel openers may have utility in the treatment of overactive bladder.
- Published
- 2004
- Full Text
- View/download PDF
36. Synthesis and structure-activity relationships of a novel series of tricyclic dihydropyridine-based KATP openers that potently inhibit bladder contractions in vitro.
- Author
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Carroll WA, Agrios KA, Altenbach RJ, Buckner SA, Chen Y, Coghlan MJ, Daza AV, Drizin I, Gopalakrishnan M, Henry RF, Kort ME, Kym PR, Milicic I, Smith JC, Tang R, Turner SC, Whiteaker KL, Zhang H, and Sullivan JP
- Subjects
- Animals, Dihydropyridines chemistry, Dihydropyridines pharmacology, Electric Stimulation, Guinea Pigs, Hemodynamics drug effects, Heterocyclic Compounds, 3-Ring chemistry, Heterocyclic Compounds, 3-Ring pharmacology, Hydrogen Bonding, In Vitro Techniques, Membrane Potentials, Muscle Contraction drug effects, Muscle, Smooth cytology, Muscle, Smooth drug effects, Muscle, Smooth physiology, Stereoisomerism, Structure-Activity Relationship, Swine, Urinary Bladder cytology, Urinary Bladder physiology, Urodynamics drug effects, Adenosine Triphosphate physiology, Dihydropyridines chemical synthesis, Heterocyclic Compounds, 3-Ring chemical synthesis, Potassium Channels drug effects, Urinary Bladder drug effects
- Abstract
Structure-activity relationships were investigated on a novel series of tricyclic dihydropyridine-containing K(ATP) openers. This diverse group of analogues, comprising a variety of heterocyclic rings fused to the dihydropyridine nucleus, was designed to determine the influence on activity of hydrogen-bond-donating and -accepting groups and their stereochemical disposition. Compounds were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a subset of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation.
- Published
- 2004
- Full Text
- View/download PDF
37. Design and synthesis of novel cyanoguanidine ATP-sensitive potassium channel openers for the treatment of overactive bladder.
- Author
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Perez-Medrano A, Buckner SA, Coghlan MJ, Gregg RJ, Gopalakrishnan M, Kort ME, Lynch JK, Scott VE, Sullivan JP, Whiteaker KL, and Carroll WA
- Subjects
- Animals, Drug Design, Guanidines pharmacology, Guanidines therapeutic use, Humans, In Vitro Techniques, Muscle, Smooth drug effects, Muscle, Smooth metabolism, Swine, Urinary Bladder drug effects, Urinary Bladder metabolism, Urinary Bladder physiology, Urinary Bladder Diseases metabolism, Adenosine Triphosphate pharmacology, Guanidines chemical synthesis, Potassium Channels metabolism, Urinary Bladder Diseases drug therapy
- Abstract
Thiourea derivatives were identified as glyburide-reversible potassium channel openers through high-throughput screening. Based on these findings, a number of novel cyanoguanidines were designed and synthesized, which hyperpolarized human bladder K(ATP) channels. These agents are potent full agonists in relaxing electrically-stimulated pig bladder strips. The synthesis, SAR and biological properties of these agents are discussed.
- Published
- 2004
- Full Text
- View/download PDF
38. Nonsteroidal selective glucocorticoid modulators: the effect of C-10 substitution on receptor selectivity and functional potency of 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines.
- Author
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Kym PR, Kort ME, Coghlan MJ, Moore JL, Tang R, Ratajczyk JD, Larson DP, Elmore SW, Pratt JK, Stashko MA, Falls HD, Lin CW, Nakane M, Miller L, Tyree CM, Miner JN, Jacobson PB, Wilcox DM, Nguyen P, and Lane BC
- Subjects
- Allyl Compounds chemistry, Allyl Compounds pharmacology, Animals, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Binding, Competitive, Carrageenan, Cell Division drug effects, Concanavalin A pharmacology, E-Selectin genetics, E-Selectin metabolism, Edema chemically induced, Edema drug therapy, Humans, In Vitro Techniques, Ligands, NF-kappa B metabolism, Protein Isoforms, Quinolines chemistry, Quinolines pharmacology, Rats, Rats, Sprague-Dawley, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Response Elements, Species Specificity, Structure-Activity Relationship, T-Lymphocytes cytology, T-Lymphocytes drug effects, Transcription Factor AP-1 metabolism, Transcription, Genetic, Allyl Compounds chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Quinolines chemical synthesis, Receptors, Glucocorticoid drug effects
- Abstract
The preparation and characterization of a series of C-10 substituted 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as a novel class of selective ligands for the glucocorticoid receptor is described. Substitution at the C-10 position of the tetracyclic core with linear, two-atom appendages (OCH(3), OCF(2)H, NHMe, SMe, CH=CH(2), Ctbd1;CH, CH(2)OH) provided molecules of high affinity (K(i) = 2-8 nM) for the human glucocorticoid receptor (hGR) with limited cross-reactivity with other steroid receptors (PR, MR, AR, ER). Optimal analogues showed slightly less potent but highly efficacious E-selectin repression with reduced levels of GRE activation efficacy in reporter gene assays relative to prednisolone. Preliminary SAR of analogues containing substitution at the C-9 and C-10 positions identified the 9-OH, 10-OMe analogue 50 and the 9-OH, 10-Cl analogue 58 as compounds that demonstrated potent, GR-mediated inhibition in a conconavalin A stimulated T-cell proliferation assay in both rodent and human whole blood monocytes. When evaluated for their in vivo effects in carrageenan-induced paw edema in rats, 50, 58, and 10-OCF(2)H analogue 35 showed dose-dependent anti-inflammatory effects (50, ED(50) = 16 mg/kg; 58, ED(50) = 15 mg/kg; 35, ED(50) = 21 mg/kg vs ED(50) = 15 mg/kg for 18 and ED(50) = 4 mg/kg for prednisolone).
- Published
- 2003
- Full Text
- View/download PDF
39. The pursuit of differentiated ligands for the glucocorticoid receptor.
- Author
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Coghlan MJ, Elmore SW, Kym PR, and Kort ME
- Subjects
- Animals, Glucocorticoids pharmacology, Humans, Ligands, Models, Molecular, Molecular Structure, Receptors, Glucocorticoid physiology, Glucocorticoids chemistry, Receptors, Glucocorticoid agonists, Receptors, Glucocorticoid antagonists & inhibitors
- Abstract
Glucocorticoids have a pervasive role in human health and physiology. The endogenous members of this family are involved in a breadth of endocrine functions including metabolism of lipids, carbohydrates and proteins, stress response, fluid and electrolyte balance, as well as maintenance of immunological, renal and skeletal homeostasis. The predominant mode of action of glucocorticoids involves regulation of gene expression via the glucocorticoid receptor (GR). Synthetic glucocorticoids have long been the standard for the treatment of inflammatory and immune disorders, yet the benefits of classic steroids such as dexamethasone and prednisolone are accompanied by well-characterized potentiation of homeostatic endocrine functions, leading to the side effects associated with prolonged treatment. In recent campaigns for safer analogs, compounds have been sought which differentiate functional repression of existing transcription factors such as AP-1 and NFkappaB from GR-mediated transcriptional activation arising from binding at glucocorticoid-receptor response elements (GREs). Such differentiated ligands would provide the desired immunoregulatory actions without the endogenous changes in gene expression associated with undifferentiated steroids. We detail the methods for the evaluation of selective GR modulators and describe the evolution of new compounds where varying degrees of selectivity have been reported.
- Published
- 2003
- Full Text
- View/download PDF
40. Enzymatic activation of DNA cleavage by dynemicin A and synthetic analogs.
- Author
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Myers AG, Kort ME, Cohen SB, and Tom NJ
- Subjects
- Anthraquinones metabolism, Anthraquinones pharmacology, Antibiotics, Antineoplastic metabolism, Antibiotics, Antineoplastic pharmacology, Biotransformation, DNA Restriction Enzymes metabolism, Electrophoresis, Polyacrylamide Gel, Enediynes, Glutathione metabolism, Molecular Structure, NAD metabolism, NADP metabolism, Oxidation-Reduction, DNA metabolism, Ferredoxin-NADP Reductase metabolism, Xanthine Oxidase metabolism
- Abstract
Dynemicin A (1), a member of the enediyne family of natural products, binds to double-stranded DNA (K(B) approximately 10(4) M(-1)) and in the presence of millimolar concentrations of a reducing cofactor such as NADPH or GSH reacts to cleave DNA. In this work, we show that the two flavin-based enzymes ferredoxin-NADP+ reductase and xanthine oxidase catalyze the reductive activation of 1 by NADPH and NADH, respectively. The enzyme-catalyzed reductive activation of 1 leads to more rapid and efficient cleavage of DNA, even with 10-20-fold lower concentrations of the stoichiometric reductant. Significantly, the enzymatic systems are also found to activate the tight-binding (K(B) > or = 10(6) M(-1)) synthetic dynemicin analogs 3 and 5 toward DNA cleavage. These same analogs do not undergo reductive activation with NADPH or NADH alone, where evidence has been obtained to support the proposal that the DNA-bound drugs are protected from reductive activation. The new enzymatic activation processes described may have important implications for chemistry occurring with 1 and synthetic analogs in vivo, as well as for the future development of dynemicin-based anticancer agents.
- Published
- 1997
- Full Text
- View/download PDF
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