Your browser doesn't support javascript.
loading
Discovery of CNS-Penetrant Apoptosis Signal-Regulating Kinase 1 (ASK1) Inhibitors.
Xin, Zhili; Himmelbauer, Martin K; Jones, J Howard; Enyedy, Istvan; Gilfillan, Rab; Hesson, Thomas; King, Kristopher; Marcotte, Douglas J; Murugan, Paramasivam; Santoro, Joseph C; Gonzalez-Lopez de Turiso, Felix.
Afiliação
  • Xin Z; Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Himmelbauer MK; Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Jones JH; Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Enyedy I; Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Gilfillan R; Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Hesson T; Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • King K; Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Marcotte DJ; Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Murugan P; Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Santoro JC; Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • Gonzalez-Lopez de Turiso F; Medicinal Chemistry, Bioassays, Drug Metabolism and Pharmacokinetics, and Physical Biochemistry and Molecular Design, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
ACS Med Chem Lett ; 11(4): 485-490, 2020 Apr 09.
Article em En | MEDLINE | ID: mdl-32292554
ABSTRACT
Apoptosis signal-regulating kinase 1 (ASK1) is a key mediator in the apoptotic and inflammatory cellular stress response. To investigate the therapeutic value of modulating this pathway in neurological disease, we have completed medicinal chemistry studies to identify novel CNS-penetrant ASK1 inhibitors starting from peripherally restricted compounds reported in the literature. This effort led to the discovery of 21, a novel ASK1 inhibitor with good potency (cell IC50 = 138 nM), low clearance (rat Cl/Clu = 0.36/6.7 L h-1 kg-1) and good CNS penetration (rat K p,uu = 0.38).
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2020 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2020 Tipo de documento: Article