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

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• 作者：Michael M. Poe ; Kashi Reddy Methuku ; Guanguan Li ; Ashwini R. Verma ; Kelly A. Teske ; Douglas C. Stafford ; Leggy A. Arnold ; Jeffrey W. Cramer ; Timothy M. Jones ; Rok Cerne ; Michael J. Krambis ; Jeffrey M. Witkin ; Enrique Jambrina ; Sabah Rehman ; Margot Ernst ; James M. Cook ; Jeffrey M. Schkeryantz
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：59
• 期：23
• 页码：10800-10806
• 全文大小：414K
• ISSN：1520-4804

文摘

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.