Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity

J Med Chem. 2001 Nov 8;44(23):3965-77. doi: 10.1021/jm0102250.

Abstract

Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC(50) = 30 nM), several additional analogues were prepared. Optimization of the C-4 anilino group of 1a led to 1c, which contains a 2,4-dichloro-5-methoxy-substituted aniline. Replacement of the methoxy group at C-7 of 1c with a 3-(morpholin-4-yl)propoxy group provided 2c, resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c with other trisubstituted anilines at C-4 were also potent Src inhibitors, and the propoxy group of 2c was preferred over ethoxy, butoxy, or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a, which had an IC(50) of 1.2 nM in the Src enzymatic assay, an IC(50) of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a, which had higher 1 and 4 h plasma levels than 2c, effectively inhibited tumor growth in xenograft models.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology
  • Cell Division / drug effects
  • Cell Line, Transformed
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fibroblasts / metabolism
  • Humans
  • Immunoblotting
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nitriles / chemical synthesis*
  • Nitriles / chemistry
  • Nitriles / pharmacokinetics
  • Nitriles / pharmacology
  • Phosphorylation
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / pharmacokinetics
  • Quinolines / pharmacology
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • Tyrosine / metabolism
  • Xenograft Model Antitumor Assays
  • src-Family Kinases / antagonists & inhibitors*

Substances

  • 4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)-3-quinolinecarbonitrile
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Nitriles
  • Piperazines
  • Quinolines
  • Tyrosine
  • src-Family Kinases