2. Academic Validation
  3. 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

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

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.
PMID: 28537398 DOI: 10.1021/acs.jmedchem.7b00211
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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