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Design and optimization of selective azaindole amide M1 positive allosteric modulators.
Davoren, Jennifer E; O'Neil, Steven V; Anderson, Dennis P; Brodney, Michael A; Chenard, Lois; Dlugolenski, Keith; Edgerton, Jeremy R; Green, Michael; Garnsey, Michelle; Grimwood, Sarah; Harris, Anthony R; Kauffman, Gregory W; LaChapelle, Erik; Lazzaro, John T; Lee, Che-Wah; Lotarski, Susan M; Nason, Deane M; Obach, R Scott; Reinhart, Veronica; Salomon-Ferrer, Romelia; Steyn, Stefanus J; Webb, Damien; Yan, Jiangli; Zhang, Lei.
Afiliación
  • Davoren JE; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States. Electronic address: jennifer.e.davoren@pfizer.com.
  • O'Neil SV; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • Anderson DP; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • Brodney MA; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • Chenard L; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • Dlugolenski K; Neuroscience and Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • Edgerton JR; Neuroscience and Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • Green M; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • Garnsey M; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • Grimwood S; Neuroscience and Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • Harris AR; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • Kauffman GW; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • LaChapelle E; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • Lazzaro JT; Primary Pharmacology Group, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • Lee CW; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • Lotarski SM; Neuroscience and Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • Nason DM; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • Obach RS; Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • Reinhart V; Neuroscience and Pain Research Unit, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • Salomon-Ferrer R; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • Steyn SJ; Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • Webb D; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
  • Yan J; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, United States.
  • Zhang L; Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Cambridge, MA 02139, United States.
Bioorg Med Chem Lett ; 26(2): 650-655, 2016 Jan 15.
Article en En | MEDLINE | ID: mdl-26631313
Selective activation of the M1 receptor via a positive allosteric modulator (PAM) is a new approach for the treatment of the cognitive impairments associated with schizophrenia and Alzheimer's disease. A novel series of azaindole amides and their key pharmacophore elements are described. The nitrogen of the azaindole core is a key design element as it forms an intramolecular hydrogen bond with the amide N-H thus reinforcing the bioactive conformation predicted by published SAR and our homology model. Representative compound 25 is a potent and selective M1 PAM that has well aligned physicochemical properties, adequate brain penetration and pharmacokinetic (PK) properties, and is active in vivo. These favorable properties indicate that this series possesses suitable qualities for further development and studies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptor Muscarínico M1 / Regulación Alostérica / Amidas / Indoles Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2016 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptor Muscarínico M1 / Regulación Alostérica / Amidas / Indoles Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2016 Tipo del documento: Article Pais de publicación: Reino Unido