Synthesis and Characterization of a Novel γ-Aminobutyric Acid Type A (GABAA) Receptor Ligand That Combines Outstanding Metabolic Stability, Pharmacokinetics, and Anxiolytic Efficacy

  • J Med Chem. 2016 Dec 8;59(23):10800-10806. doi: 10.1021/acs.jmedchem.6b01332.
Michael M Poe  1 ,  Kashi Reddy Methuku  1 ,  Guanguan Li  1 ,  Ashwini R Verma  1 ,  Kelly A Teske  1 ,  Douglas C Stafford  1 ,  Leggy A Arnold  1 ,  Jeffrey W Cramer  2 ,  Timothy M Jones  2 ,  Rok Cerne  2 ,  Michael J Krambis  2 ,  Jeffrey M Witkin  2 ,  Enrique Jambrina  3 ,  Sabah Rehman  4 ,  Margot Ernst  4 ,  James M Cook  1 ,  Jeffrey M Schkeryantz  2
Affiliations
  • 1. Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
  • 2. Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
  • 3. Lilly Research Laboratories, Eli Lilly and Company , 28108 Alcobendas, Spain.
  • 4. Department for Molecular Neurosciences, Medical University of Vienna , 1090 Vienna, Austria.
PMID: 27933953 DOI: 10.1021/acs.jmedchem.6b01332
Abstract

1,4-Benzodiazepines are used in the treatment of anxiety disorders but have limited long-term use due to adverse effects. HZ-166 (2) has been shown to have anxiolytic-like effects with reduced sedative/ataxic liabilities. A 1,3-oxazole KRM-II-81 (9) was discovered from a series of six bioisosteres with significantly improved pharmacokinetic and pharmacodynamic properties as compared to 2. Oxazole 9 was further characterized and exhibited improved anxiolytic-like effects in a mouse marble burying assay and a rat Vogel conflict test.