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

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

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.

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