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Your search keyword '"Kelly MJ 3rd"' showing total 2 results
Start Over Author "Kelly MJ 3rd" Journal bioorganic medicinal chemistry letters
2 results on '"Kelly MJ 3rd"'

1. Benzoxazolinone aryl sulfonamides as potent, selective Na v 1.7 inhibitors with in vivo efficacy in a preclinical pain model.

Author

Pero JE, Rossi MA, Lehman HDGF, Kelly MJ 3rd, Mulhearn JJ, Wolkenberg SE, Cato MJ, Clements MK, Daley CJ, Filzen T, Finger EN, Gregan Y, Henze DA, Jovanovska A, Klein R, Kraus RL, Li Y, Liang A, Majercak JM, Panigel J, Urban MO, Wang J, Wang YH, Houghton AK, and Layton ME

Subjects
Administration, Oral, Analgesics administration & dosage, Analgesics chemistry, Animals, Benzoxazoles administration & dosage, Benzoxazoles chemistry, Biological Availability, Disease Models, Animal, Dose-Response Relationship, Drug, Formaldehyde administration & dosage, Humans, Mice, Molecular Structure, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle metabolism, Pain chemically induced, Rats, Structure-Activity Relationship, Sulfonamides administration & dosage, Sulfonamides chemistry, Analgesics pharmacology, Benzoxazoles pharmacology, NAV1.7 Voltage-Gated Sodium Channel metabolism, Pain drug therapy, Sulfonamides pharmacology
Abstract

Studies on human genetics have suggested that inhibitors of the Na v 1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Na v 1.7 inhibitors with excellent selectivity against the Na v 1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Na v 1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Published
2017
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2. Discovery of 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as positive allosteric modulators of metabotropic glutamate subtype-2 (mGlu2) receptors with efficacy in a preclinical model of psychosis.

Author

Layton ME, Reif AJ, Hartingh TJ, Rodzinak K, Dudkin V, Wang C, Arrington K, Kelly MJ 3rd, Garbaccio RM, O'Brien JA, Magliaro BC, Uslaner JM, Huszar SL, Fillgrove KL, Tang C, Kuo Y, and Jacobson MA

Subjects
Allosteric Regulation, Animals, Disease Models, Animal, Drug Evaluation, Preclinical, Imidazoles blood, Imidazoles pharmacology, Imidazoles therapeutic use, Locomotion drug effects, Protein Binding, Psychotic Disorders drug therapy, Psychotic Disorders pathology, Pyridines pharmacology, Pyridines therapeutic use, Pyridones blood, Pyridones pharmacology, Rats, Receptors, Metabotropic Glutamate metabolism, Structure-Activity Relationship, Imidazoles chemistry, Pyridines chemistry, Pyridones chemistry, Receptors, Metabotropic Glutamate chemistry
Abstract

Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic investigation of aryl-SAR led to the identification of compound 27 as a potent and highly selective mGlu2 PAM with sufficient pharmacokinetics to advance to preclinical models of psychosis. Gratifyingly, compound 27 showed full efficacy in the PCP- and MK-801-induced hyperlocomotion assay in rats at CSF concentrations consistent with mGlu2 PAM potency., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Published
2016
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