Discovery of Clinical Candidate BMS-823778 as an Inhibitor of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1)

  • ACS Med Chem Lett. 2018 Nov 13;9(12):1170-1174. doi: 10.1021/acsmedchemlett.8b00307.
Jun Li  1 ,  Lawrence J Kennedy  1 ,  Steven J Walker  1 ,  Haixia Wang  1 ,  James J Li  1 ,  Zhenqiu Hong  1 ,  Stephen P O'Connor  1 ,  Xiang-Yang Ye  1 ,  Stephanie Chen  1 ,  Shung Wu  1 ,  David S Yoon  1 ,  Akbar Nayeem  2 ,  Daniel M Camac  2 ,  Vidhyashankar Ramamurthy  2 ,  Paul E Morin  2 ,  Steven Sheriff  2 ,  Mengmeng Wang  1 ,  Timothy W Harper  1 ,  Rajasree Golla  1 ,  Ramakrishna Seethala  1 ,  Thomas Harrity  1 ,  Randolph P Ponticiello  1 ,  Nathan N Morgan  1 ,  Joseph R Taylor  1 ,  Rachel Zebo  1 ,  Brad Maxwell  2 ,  Frederick Moulin  1 ,  David A Gordon  1 ,  Jeffrey A Robl  1
Affiliations
  • 1. Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, United States.
  • 2. Research & Development, Bristol-Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08543, United States.
PMID: 30613321 DOI: 10.1021/acsmedchemlett.8b00307
Abstract

BMS-823778 (2), 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 (IC50 = 2.3 nM) with >10,000-fold selectivity over 11β-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.

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