title: 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).
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).
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Yang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: T G Murali
authors.initials: TG
authors.lastname: Dhar
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Zili
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Hai-Yun
authors.initials: HY
authors.lastname: Xiao
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: James J-W
authors.initials: JJ
authors.lastname: Duan
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Galella
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Cunningham
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Sium
authors.initials: S
authors.lastname: Habte
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: David
authors.initials: D
authors.lastname: Shuster
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Kim W
authors.initials: KW
authors.lastname: McIntyre
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Julie
authors.initials: J
authors.lastname: Carman
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Holloway
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Somerville
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Nadler
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Luisa
authors.initials: L
authors.lastname: Salter-Cid
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Weinstein
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001769:Blood / Q000187:drug effects / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004355:Drug Stability; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011917:Rats, Inbred Lew; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C000600967:BMS-341; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D011965:Receptors, Glucocorticoid; D013830:Thiadiazoles; D018808:Transcription Factor AP-1; D051544:Cytochrome P-450 CYP3A