BMS-823778 (), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) enzyme (IC = 2.3 nM) with >10,000-fold selectivity over 11β-HSD-2. Compound exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED = 34 mg/kg). Compound also showed excellent inhibition in an adipose DIO mouse model (ED = 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 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295842PMC
http://dx.doi.org/10.1021/acsmedchemlett.8b00307DOI Listing

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