Placebo-Controlled, Double-Blind, Ascending Single and Multiple Oral Dose Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of BMS-791826 and to Assess Its Marker Specific Pharmacodynamics in Relation to Prednisolone in Healthy Males

The purpose of this study is to evaluate the safety, PK, PD, of BMS-791826 and to assess its marker specific PD in relation to Prednisolone in healthy male subjects

Start Date11 Nov 2008

Sponsor / Collaborator

Bristol Myers Squibb Co.

100 Clinical Results associated with BMS-791826

100 Translational Medicine associated with BMS-791826

100 Patents (Medical) associated with BMS-791826

Literatures (Medical) associated with BMS-791826

27 Oct 2011·Journal of Medicinal ChemistryQ1 · MEDICINE

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)

Q1 · MEDICINE

Article

Author: Holloway, Deborah A. ; Nadler, Steven G. ; Salter-Cid, Luisa ; Weinstein, David S. ; Burke, Christine ; Gao, Ling ; Somerville, John E. ; Guarino, Victor ; Carman, Julie ; Dodd, John H. ; Doweyko, Arthur M. ; Habte, Sium ; Shuster, David ; Wang, Jin Hong ; Cunningham, Mark ; Gong, Hua ; Barrish, Joel C.

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.

100 Deals associated with BMS-791826

External Link

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