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

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

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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