Improving the pharmacokinetic and CYP inhibition profiles of azaxanthene-based glucocorticoid receptor modulators-identification of (S)-5-(2-(9-fluoro-2-(4-(2-hydroxypropan-2-yl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanamido)-N-(tetrahydro-2H-pyran-4-yl)-1,3,4-thiadiazole-2-carboxamide (BMS-341)

Michael G Yang; T G Murali Dhar; Zili Xiao; Hai-Yun Xiao; James J-W Duan; Bin Jiang; Michael A Galella; Mark Cunningham; Jinhong Wang; Sium Habte; David Shuster; Kim W McIntyre; Julie Carman; Deborah A Holloway; John E Somerville; Steven G Nadler; Luisa Salter-Cid; Joel C Barrish; David S Weinstein

doi:10.1021/acs.jmedchem.5b00257

Improving the pharmacokinetic and CYP inhibition profiles of azaxanthene-based glucocorticoid receptor modulators-identification of (S)-5-(2-(9-fluoro-2-(4-(2-hydroxypropan-2-yl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanamido)-N-(tetrahydro-2H-pyran-4-yl)-1,3,4-thiadiazole-2-carboxamide (BMS-341)

J Med Chem. 2015 May 28;58(10):4278-90. doi: 10.1021/acs.jmedchem.5b00257. Epub 2015 May 7.

Authors

Michael G Yang¹, T G Murali Dhar¹, Zili Xiao¹, Hai-Yun Xiao¹, James J-W Duan¹, Bin Jiang¹, Michael A Galella¹, Mark Cunningham¹, Jinhong Wang¹, Sium Habte¹, David Shuster¹, Kim W McIntyre¹, Julie Carman¹, Deborah A Holloway¹, John E Somerville¹, Steven G Nadler¹, Luisa Salter-Cid¹, Joel C Barrish¹, David S Weinstein¹

Affiliation

¹ Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.

PMID: 25905990
DOI: 10.1021/acs.jmedchem.5b00257

Abstract

An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively).

MeSH terms

Animals
Arthritis, Experimental / drug therapy*
Blood / drug effects
Blood / metabolism
Chemistry Techniques, Synthetic
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors / chemistry
Cytochrome P-450 CYP3A Inhibitors / pharmacology
Cytochrome P-450 Enzyme Inhibitors / chemistry
Cytochrome P-450 Enzyme Inhibitors / pharmacokinetics
Cytochrome P-450 Enzyme Inhibitors / pharmacology*
Disease Models, Animal
Dogs
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical / methods
Drug Stability
Heterocyclic Compounds, 3-Ring / chemistry
Heterocyclic Compounds, 3-Ring / pharmacokinetics
Heterocyclic Compounds, 3-Ring / pharmacology*
Humans
Male
Rats, Inbred Lew
Receptors, Glucocorticoid / agonists
Receptors, Glucocorticoid / metabolism*
Structure-Activity Relationship
Thiadiazoles / chemistry
Thiadiazoles / pharmacokinetics
Thiadiazoles / pharmacology*
Transcription Factor AP-1 / metabolism

Substances

BMS-341
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Heterocyclic Compounds, 3-Ring
Receptors, Glucocorticoid
Thiadiazoles
Transcription Factor AP-1
Cytochrome P-450 CYP3A