Your browser doesn't support javascript.
loading
Bicyclo((aryl)methyl)benzamides as inhibitors of GlyT1.
Varnes, Jeffrey G; Xiong, Hui; Forst, Janet M; Holmquist, Christopher R; Ernst, Glen E; Frietze, William; Dembofsky, Bruce; Andisik, Don W; Palmer, William E; Hinkley, Lindsay; Steelman, Gary B; Wilkins, Deidre E; Tian, Gaochao; Jonak, Gerald; Potts, William M; Wang, Xia; Brugel, Todd A; Alhambra, Cristóbal; Wood, Michael W; Veale, Chris A; Albert, Jeffrey S.
Afiliação
  • Varnes JG; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA. Electronic address: jeffrey.varnes@astrazeneca.com.
  • Xiong H; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Forst JM; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Holmquist CR; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Ernst GE; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Frietze W; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Dembofsky B; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Andisik DW; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Palmer WE; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Hinkley L; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Steelman GB; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Wilkins DE; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Tian G; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Jonak G; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Potts WM; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Wang X; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Brugel TA; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Alhambra C; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Wood MW; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Veale CA; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA.
  • Albert JS; Medicinal Chemistry, Neuroscience, IMED Biotech Unit, AstraZeneca, Wilmington, DE, USA. Electronic address: jeffrey.albert@intellisynrd.com.
Bioorg Med Chem Lett ; 28(6): 1043-1049, 2018 04 01.
Article em En | MEDLINE | ID: mdl-29486970
ABSTRACT
A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 µmol/kg compared to control.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Benzamidas / Compostos Bicíclicos com Pontes / Proteínas da Membrana Plasmática de Transporte de Glicina Idioma: En Ano de publicação: 2018 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Benzamidas / Compostos Bicíclicos com Pontes / Proteínas da Membrana Plasmática de Transporte de Glicina Idioma: En Ano de publicação: 2018 Tipo de documento: Article