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Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis.
Shipe, William D; Sharik, Steven S; Barrow, James C; McGaughey, Georgia B; Theberge, Cory R; Uslaner, Jason M; Yan, Youwei; Renger, John J; Smith, Sean M; Coleman, Paul J; Cox, Christopher D.
Afiliação
  • Shipe WD; Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Sharik SS; Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Barrow JC; Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • McGaughey GB; Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Theberge CR; Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Uslaner JM; Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Yan Y; Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Renger JJ; Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Smith SM; Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Coleman PJ; Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
  • Cox CD; Departments of †Discovery Chemistry, ‡Chemistry Modeling and Informatics, §Neuroscience, and ∥Structural Chemistry, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
J Med Chem ; 58(19): 7888-94, 2015 Oct 08.
Article em En | MEDLINE | ID: mdl-26378882
ABSTRACT
Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Fosfodiesterase / Relação Estrutura-Atividade Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Animals / Humans / Male Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores de Fosfodiesterase / Relação Estrutura-Atividade Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Animals / Humans / Male Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2015 Tipo de documento: Article País de afiliação: Estados Unidos