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Synthesis and Characterization of a Novel γ-Aminobutyric Acid Type A (GABAA) Receptor Ligand That Combines Outstanding Metabolic Stability, Pharmacokinetics, and Anxiolytic Efficacy.
Poe, Michael M; Methuku, Kashi Reddy; Li, Guanguan; Verma, Ashwini R; Teske, Kelly A; Stafford, Douglas C; Arnold, Leggy A; Cramer, Jeffrey W; Jones, Timothy M; Cerne, Rok; Krambis, Michael J; Witkin, Jeffrey M; Jambrina, Enrique; Rehman, Sabah; Ernst, Margot; Cook, James M; Schkeryantz, Jeffrey M.
Afiliação
  • Poe MM; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
  • Methuku KR; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
  • Li G; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
  • Verma AR; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
  • Teske KA; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
  • Stafford DC; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
  • Arnold LA; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
  • Cramer JW; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
  • Jones TM; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
  • Cerne R; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
  • Krambis MJ; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
  • Witkin JM; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
  • Jambrina E; Lilly Research Laboratories, Eli Lilly and Company , 28108 Alcobendas, Spain.
  • Rehman S; Department for Molecular Neurosciences, Medical University of Vienna , 1090 Vienna, Austria.
  • Ernst M; Department for Molecular Neurosciences, Medical University of Vienna , 1090 Vienna, Austria.
  • Cook JM; Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee , Milwaukee, Wisconsin 53201, United States.
  • Schkeryantz JM; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 42685, United States.
J Med Chem ; 59(23): 10800-10806, 2016 12 08.
Article em En | MEDLINE | ID: mdl-27933953
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxazóis / Ansiolíticos / Benzodiazepinas / Receptores de GABA-A / Antagonistas de Receptores de GABA-A / Imidazóis Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxazóis / Ansiolíticos / Benzodiazepinas / Receptores de GABA-A / Antagonistas de Receptores de GABA-A / Imidazóis Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article