Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity.
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.
Boschelli
D H
DH
Chemical Sciences, Wyeth-Ayerst Research, 401 North Middletown Road, Pearl River, New York 10965, USA. bosched@war.wyeth.com
Ye
F
F
Wang
Y D
YD
Dutia
M
M
Johnson
S L
SL
Wu
B
B
Miller
K
K
Powell
D W
DW
Yaczko
D
D
Young
M
M
Tischler
M
M
Arndt
K
K
Discafani
C
C
Etienne
C
C
Gibbons
J
J
Grod
J
J
Lucas
J
J
Weber
J M
JM
Boschelli
F
F
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010766:Phosphorylation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C439965:4-((2,4-dichloro-5-methoxyphenyl)amino)-6-methoxy-7-(3-(4-methyl-1-piperazinyl)propoxy)-3-quinolinecarbonitrile; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009570:Nitriles; D010879:Piperazines; D011804:Quinolines; D014443:Tyrosine; D019061:src-Family Kinases