Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor

  • J Med Chem. 2017 Jun 22;60(12):4932-4948. doi: 10.1021/acs.jmedchem.7b00211.
Xiang-Yang Ye  1  2 Stephanie Y Chen  1  2 Shung Wu  1  2 David S Yoon  1  2 Haixia Wang  1  2 Zhenqiu Hong  1  2 Stephen P O'Connor  1  2 Jun Li  1  2 James J Li  1  2 Lawrence J Kennedy  1  2 Steven J Walker  1  2 Akbar Nayeem  1  2 Steven Sheriff  1  2 Daniel M Camac  1  2 Vidyhashankar Ramamurthy  1  2 Paul E Morin  1  2 Rachel Zebo  1  2 Joseph R Taylor  1  2 Nathan N Morgan  1  2 Randolph P Ponticiello  1  2 Thomas Harrity  1  2 Atsu Apedo  1  2 Rajasree Golla  1  2 Ramakrishna Seethala  1  2 Mengmeng Wang  1  2 Timothy W Harper  1  2 Bogdan G Sleczka  1  2 Bin He  1  2 Mark Kirby  1  2 David K Leahy  1  2 Jianqing Li  1  2 Ronald L Hanson  1  2 Zhiwei Guo  1  2 Yi-Xin Li  1  2 John D DiMarco  1  2 Raymond Scaringe  1  2 Brad Maxwell  1  2 Frederick Moulin  1  2 Joel C Barrish  1  2 David A Gordon  1  2 Jeffrey A Robl  1  2
Affiliations
  • 1. Discovery Chemistry, ‡Pharmaceutical Candidate Optimization, §Computer-Assisted Drug Design, ∥Metabolic Diseases Biology, ⊥Lead Evaluation, #Process Chemistry, ∇Chemical Synthesis, ○Discovery Toxicology, Research and Development, Bristol-Myers Squibb , 350 Carter Road, Princeton, New Jersey 08540, United States.
  • 2. Molecular Structure and Design, ¶Protein Science, +Solid State Chemistry, Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
Abstract

BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11β-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and Other human diseases modulated by glucocorticoid control.

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