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Publication Abstract from PubMed

BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11beta-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.

Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD-1).,Li J, Kennedy LJ, Walker SJ, Wang H, Li JJ, Hong Z, O'Connor SP, Ye XY, Chen S, Wu S, Yoon DS, Nayeem A, Camac DM, Ramamurthy V, Morin PE, Sheriff S, Wang M, Harper TW, Golla R, Seethala R, Harrity T, Ponticiello RP, Morgan NN, Taylor JR, Zebo R, Maxwell B, Moulin F, Gordon DA, Robl JA ACS Med Chem Lett. 2018 Nov 13;9(12):1170-1174. doi:, 10.1021/acsmedchemlett.8b00307. eCollection 2018 Dec 13. PMID:30613321^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.