Synthesis and Src kinase inhibitory activity of a series of 4-phenylamino-3-quinolinecarbonitriles.
Screening of a directed compound library in a yeast-based assay identified 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (2a) as a Src inhibitor. An enzymatic assay established that 2a was an ATP-competitive inhibitor of the kinase activity of Src. We present here SAR data for 2a which shows that the aniline group at C-4, the carbonitrile group at C-3, and the alkoxy groups at C-6 and C-7 of the quinoline are crucial for optimal activity. Increasing the size of the C-2 substituent of the aniline at C-4 of 2a from chloro to bromo to iodo resulted in a corresponding increase in Src inhibition. Furthermore, replacement of the 7-methoxy group of 2a with various 3-heteroalkylaminopropoxy groups provided increased inhibition of both Src enzymatic and cellular activity. Compound 25, which contains a 3-morpholinopropoxy group, had an IC(50) of 3.8 nM in the Src enzymatic assay and an IC(50) of 940 nM for the inhibition of Src-dependent cell proliferation.
Chemical Sciences and Oncology, Wyeth-Ayerst Research, 401 North Middletown Road, Pearl River, New York 10965, USA. bosched@war.wyeth.com
D H
DH
Boschelli
Y D
YD
Wang
F
F
Ye
B
B
Wu
N
N
Zhang
M
M
Dutia
D W
DW
Powell
A
A
Wissner
K
K
Arndt
J M
JM
Weber
F
F
Boschelli
D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
C423350:4-((2,4-dichlorophenyl)aminio)-6-methoxy-7-(3-morpholin-4-ylpropoxy)-3-quinolinecarbonitrile; D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D009025:Morpholines; D009570:Nitriles; D011804:Quinolines; D019061:src-Family Kinases