title: Azaxanthene based selective glucocorticoid receptor modulators: design, synthesis, and pharmacological evaluation of (S)-4-(5-(1-((1,3,4-thiadiazol-2-yl)amino)-2-methyl-1-oxopropan-2-yl)-5H-chromeno[2,3-b]pyridin-2-yl)-2-fluoro-N,N-dimethylbenzamide (BMS-776532) and its methylene homologue (BMS-791826).
abstract: Structurally novel 5H-chromeno[2,3-b]pyridine (azaxanthene) selective glucocorticoid receptor (GR) modulators have been identified. A screening paradigm utilizing cellular assays of GR-mediated transrepression of proinflammatory transcription factors and transactivation of GR-dependent genes combined with three physiologically relevant assays of cytokine induction in human whole blood has allowed for the identification of high affinity, selective GR ligands that display a broad range of pharmacological profiles. Agonist efficacy in reporter assays can be tuned by halogenation of a pendent phenyl ring and correlates well with efficacy for cytokine inhibition in human whole blood. A hypothetical binding mode is proposed, invoking an expanded ligand binding pocket resembling that of arylpyrazole-bound GR structures. Two compounds of close structural similarity (35 and 37; BMS-776532 and BMS-791826, respectively) have been found to maintain distinct and consistent levels of partial agonist efficacy across several assays, displaying anti-inflammatory activity comparable to that of prednisolone 2 in suppressing cytokine production in whole blood and in rodent models of acute and chronic inflammation.
authors: Research and Development, Bristol-Myers Squibb Company, Princeton, New Jersey 08543-4000, United States. David.Weinstein@bms.com
authors: David S
authors: DS
authors: Weinstein
authors: Hua
authors: H
authors: Gong
authors: Arthur M
authors: AM
authors: Doweyko
authors: Mark
authors: M
authors: Cunningham
authors: Sium
authors: S
authors: Habte
authors: Jin Hong
authors: JH
authors: Wang
authors: Deborah A
authors: DA
authors: Holloway
authors: Christine
authors: C
authors: Burke
authors: Ling
authors: L
authors: Gao
authors: Victor
authors: V
authors: Guarino
authors: Julie
authors: J
authors: Carman
authors: John E
authors: JE
authors: Somerville
authors: David
authors: D
authors: Shuster
authors: Luisa
authors: L
authors: Salter-Cid
authors: John H
authors: JH
authors: Dodd
authors: Steven G
authors: SG
authors: Nadler
authors: Joel C
authors: JC
authors: Barrish
mesh_terms: D000469:Alkaline Phosphatase / Q000096:biosynthesis; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D045744:Cell Line, Tumor; D054333:Drug Partial Agonism; D004487:Edema / Q000188:drug therapy; D005974:Glutamate-Ammonia Ligase / Q000096:biosynthesis; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D008958:Models, Molecular; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014444:Tyrosine Transaminase / Q000096:biosynthesis
chemical_list: C568959:2-(4-((dimethylamino)carbonyl)-3-fluorophenyl)-alpha,alpha-dimethyl-N-1,3,4-thiadiazol-2-yl-5H-(1)benzopyrano(2,3-b)pyridin-5-acetamide; C568960:5-2-(4-((ethylmethylamino)carbonyl)-3-fluorophenyl)-alpha,alpha-dimethyl-N-1,3,4-thiadiazol-2-yl-5H-(1)benzopyrano(2,3-b)pyridin-5-acetamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D006575:Heterocyclic Compounds, 3-Ring; D053583:Interleukin-1beta; D011965:Receptors, Glucocorticoid; D013830:Thiadiazoles; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D014444:Tyrosine Transaminase; D000469:Alkaline Phosphatase; D005974:Glutamate-Ammonia Ligase