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

Xiang-Yang Ye; Stephanie Y Chen; Shung Wu; David S Yoon; Haixia Wang; Zhenqiu Hong; Stephen P O'Connor; Jun Li; James J Li; Lawrence J Kennedy; Steven J Walker; Akbar Nayeem; Steven Sheriff; Daniel M Camac; Vidyhashankar Ramamurthy; Paul E Morin; Rachel Zebo; Joseph R Taylor; Nathan N Morgan; Randolph P Ponticiello; Thomas Harrity; Atsu Apedo; Rajasree Golla; Ramakrishna Seethala; Mengmeng Wang; Timothy W Harper; Bogdan G Sleczka; Bin He; Mark Kirby; David K Leahy; Jianqing Li; Ronald L Hanson; Zhiwei Guo; Yi-Xin Li; John D DiMarco; Raymond Scaringe; Brad Maxwell; Frederick Moulin; Joel C Barrish; David A Gordon; Jeffrey A Robl

doi:10.1021/acs.jmedchem.7b00211

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. Epub 2017 Jun 5.

Authors

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.

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / chemistry
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Actins / antagonists & inhibitors
Adamantane / administration & dosage
Adamantane / analogs & derivatives*
Adamantane / chemistry
Adamantane / pharmacology
Administration, Oral
Animals
Azetidines / administration & dosage
Azetidines / chemistry
Azetidines / pharmacology*
Biological Availability
Crystallography, X-Ray
Dogs
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Female
Half-Life
Humans
Hypothalamo-Hypophyseal System / drug effects
Inhibitory Concentration 50
Macaca fascicularis
Male
Mice, Obese
Rats
Structure-Activity Relationship

Substances

ACTL9 protein, human
Actins
Azetidines
BMS-816336
Enzyme Inhibitors
11-beta-Hydroxysteroid Dehydrogenase Type 1
Adamantane