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

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.

SUBMITTER: Poe MM

PROVIDER: S-EPMC5215686 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Synthesis and Characterization of a Novel γ-Aminobutyric Acid Type A (GABA<sub>A</sub>) Receptor Ligand That Combines Outstanding Metabolic Stability, Pharmacokinetics, and Anxiolytic Efficacy.

Poe Michael M MM Methuku Kashi Reddy KR Li Guanguan G Verma Ashwini R AR Teske Kelly A KA Stafford Douglas C DC Arnold Leggy A LA Cramer Jeffrey W JW Jones Timothy M TM Cerne Rok R Krambis Michael J MJ Witkin Jeffrey M JM Jambrina Enrique E Rehman Sabah S Ernst Margot M Cook James M JM Schkeryantz Jeffrey M JM

Journal of medicinal chemistry 20161128 23

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 ...[more]

PMID: 27933953

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