2. Academic Validation
  3. Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity

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.
D H Boschelli 1,  F Ye,  Y D Wang,  M Dutia,  S L Johnson,  B Wu,  K Miller,  D W Powell,  D Yaczko,  M Young,  M Tischler,  K Arndt,  C Discafani,  C Etienne,  J Gibbons,  J Grod,  J Lucas,  J M Weber,  F Boschelli
Affiliations

Affiliation

  • 1 Chemical Sciences, Wyeth-Ayerst Research, 401 North Middletown Road, Pearl River, New York 10965, USA. bosched@war.wyeth.com
PMID: 11689083 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.

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