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MARK inhibitors: Declaring a No-Go decision on a chemical series based on extensive DMPK experimentation.
Haidle, Andrew M; Childers, Kaleen K; Zabierek, Anna A; Katz, Jason D; Jewell, James P; Hou, Yongquan; Altman, Michael D; Szewczak, Alexander; Chen, Dapeng; Harsch, Andreas; Hayashi, Mansuo; Warren, Lee; Hutton, Michael; Nuthall, Hugh; Stanton, Matt G; Davies, Ian W; Munoz, Ben; Northrup, Alan.
Afiliação
  • Haidle AM; Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Childers KK; Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Zabierek AA; Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Katz JD; Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Jewell JP; Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Hou Y; Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Altman MD; Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Szewczak A; Department of In Vitro Sciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Chen D; Department of Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Harsch A; Department of Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Hayashi M; Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Warren L; Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Hutton M; Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Nuthall H; Department of Neuroscience, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Stanton MG; Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Davies IW; Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Munoz B; Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
  • Northrup A; Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Bioorg Med Chem Lett ; 27(1): 109-113, 2017 01 01.
Article em En | MEDLINE | ID: mdl-27894874
ABSTRACT
Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer's disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro-in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinonas / Pirróis / Inibidores de Proteínas Quinases / Doença de Alzheimer Limite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2017 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: Pirimidinonas / Pirróis / Inibidores de Proteínas Quinases / Doença de Alzheimer Limite: Animals / Humans Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos