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Indole acids as a novel PDE2 inhibitor chemotype that demonstrate pro-cognitive activity in multiple species.
Stachel, Shawn J; Egbertson, Melissa S; Wai, Jenny; Machacek, Michelle; Toolan, Dawn M; Swestock, John; Eddins, Donnie M; Puri, Vanita; McGaughey, Georgia; Su, Hua-Poo; Perlow, Debbie; Wang, Deping; Ma, Lei; Parthasarathy, Gopal; Reid, John C; Abeywickrema, Pravien D; Smith, Sean M; Uslaner, Jason M.
Afiliação
  • Stachel SJ; Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA. Electronic address: shawn_stachel@merck.com.
  • Egbertson MS; Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • Wai J; Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • Machacek M; Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • Toolan DM; Department of Neuroscience, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • Swestock J; Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • Eddins DM; Department of Pharmacology, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • Puri V; Department of Pharmacology, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • McGaughey G; Department of Structural Biology, Merck & Co. Inc, PO Box 4, West Point, PA 19486, USA.
  • Su HP; Department of Structural Biology, Merck & Co. Inc, PO Box 4, West Point, PA 19486, USA.
  • Perlow D; Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • Wang D; Department of Structural Biology, Merck & Co. Inc, PO Box 4, West Point, PA 19486, USA.
  • Ma L; Department of Neuroscience, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • Parthasarathy G; Department of Structural Biology, Merck & Co. Inc, PO Box 4, West Point, PA 19486, USA.
  • Reid JC; Department of Structural Biology, Merck & Co. Inc, PO Box 4, West Point, PA 19486, USA.
  • Abeywickrema PD; Department of Structural Biology, Merck & Co. Inc, PO Box 4, West Point, PA 19486, USA.
  • Smith SM; Department of Neuroscience, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
  • Uslaner JM; Department of Neuroscience, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
Bioorg Med Chem Lett ; 28(6): 1122-1126, 2018 04 01.
Article em En | MEDLINE | ID: mdl-29534798
ABSTRACT
An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Inibidores de Fosfodiesterase / Ácido Acético / Nucleotídeo Cíclico Fosfodiesterase do Tipo 2 / Disfunção Cognitiva / Indóis Limite: Animals Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2018 Tipo de documento: Article
Texto completo
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XML
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Inibidores de Fosfodiesterase / Ácido Acético / Nucleotídeo Cíclico Fosfodiesterase do Tipo 2 / Disfunção Cognitiva / Indóis Limite: Animals Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2018 Tipo de documento: Article