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Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI.

Authors
  • Pero, Joseph E1
  • Rossi, Michael A1
  • Kelly, Michael J 3rd1
  • Lehman, Hannah D G F1
  • Layton, Mark E1
  • Garbaccio, Robert M1
  • O'Brien, Julie A1
  • Magliaro, Brian C1
  • Uslaner, Jason M1
  • Huszar, Sarah L1
  • Fillgrove, Kerry L1
  • Tang, Cuyue1
  • Kuo, Yuhsin1
  • Joyce, Leo A1
  • Sherer, Edward C1
  • Jacobson, Marlene A1
  • 1 Departments of Medicinal Chemistry, In Vitro Sciences, Psychiatry Research, Central Pharmacology, Drug Metabolism, Process and Analytical Chemistry, and Structural Chemistry, Merck Research Laboratories , P.O. Box 4, Sumneytown Pike, West Point, Pennsylvania 19486, United States. , (United States)
Type
Published Article
Journal
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society
Publication Date
Mar 10, 2016
Volume
7
Issue
3
Pages
312–317
Identifiers
DOI: 10.1021/acsmedchemlett.5b00459
PMID: 26985321
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Investigation of a novel amino-aza-benzimidazolone structural class of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2) identified [2.2.2]-bicyclic amine 12 as an intriguing lead structure due to its promising physicochemical properties and lipophilic ligand efficiency (LLE). Further optimization led to chiral amide 18, which exhibited strong in vitro activity and attractive pharmacokinetic (PK) properties. Hypothesis-driven target design identified compound 21 as a potent, highly selective, orally bioavailable mGluR2 PAM, which addressed a CYP time-dependent inhibition (TDI) liability of 18, while maintaining excellent drug-like properties with robust in vivo activity in a clinically validated model of antipsychotic potential.

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