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Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition.
Wood, Michael R; Noetzel, Meredith J; Tarr, James C; Rodriguez, Alice L; Lamsal, Atin; Chang, Sichen; Foster, Jarrett J; Smith, Emery; Chase, Peter; Hodder, Peter S; Engers, Darren W; Niswender, Colleen M; Brandon, Nicholas J; Wood, Michael W; Duggan, Mark E; Conn, P Jeffrey; Bridges, Thomas M; Lindsley, Craig W.
Afiliação
  • Wood MR; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • Noetzel MJ; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Tarr JC; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Rodriguez AL; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Lamsal A; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Chang S; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Foster JJ; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Smith E; The Scripps Research Institutes Molecular Screening Center, Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
  • Chase P; The Scripps Research Institutes Molecular Screening Center, Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
  • Hodder PS; Amgen Inc., Thousand Oaks, CA 91320, USA.
  • Engers DW; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Niswender CM; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37
  • Brandon NJ; Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
  • Wood MW; Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
  • Duggan ME; Neuroscience Innovative Medicines, Astra Zeneca, 141 Portland Street, Cambridge, MA 02139, USA.
  • Conn PJ; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37
  • Bridges TM; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: thomas.m.bridges@vanderbilt.edu.
  • Lindsley CW; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic
Bioorg Med Chem Lett ; 26(17): 4282-6, 2016 09 01.
Article em En | MEDLINE | ID: mdl-27476142
ABSTRACT
This Letter describes the chemical optimization of a novel series of M4 PAMs based on a non-enolizable ketone core, identified from an MLPCN functional high-throughput screen. The HTS hit was potent, selective and CNS penetrant; however, the compound was highly cleared in vitro and in vivo. SAR provided analogs for which M4 PAM potency and CNS exposure were maintained; yet, clearance remained high. Metabolite identification studies demonstrated that this series was subject to rapid, and near quantitative, reductive metabolism to the corresponding secondary alcohol metabolite that was devoid of M4 PAM activity.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor Muscarínico M1 / Descoberta de Drogas / Cetonas Limite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor Muscarínico M1 / Descoberta de Drogas / Cetonas Limite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos