Synthesis and Src kinase inhibitory activity of a series of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-furyl-3-quinolinecarbonitriles.
Compound 1 (SKI-606, bosutinib), a 7-alkoxy-4-[(2,4-dichloro-5-methoxyphenyl)amino]-3-quinolinecarbonitrile, is a potent inhibitor of Src kinase activity. We previously reported that analogs of 1 with thiophene groups at C-7 retained the Src activity of the parent compound. The corresponding C-7 furan analogs were prepared and it was found that the 3,5-substituted furan analog had increased activity compared to that of the 2,5-substituted furan isomer. Addition of a methoxy group at C-6 decreased the Src inhibitory activity of the C-7 2,5-substituted furan analog but increased the activity of the C-7 3,5-substituted furan isomer. This compound, 10, was a more potent Src inhibitor than 1 in both enzymatic and cell-based assays. The kinase selectivity profile of 10 was similar to that of 1, with 10 also inhibiting the activity of Abl and Lck. When tested in a solid tumor xenograft model, 10 had comparable oral activity to that of 1.
Boschelli
Diane H
DH
Chemical and Screening Sciences and Oncology, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA. bosched@wyeth.com
Wu
Biqi
B
Ye
Fei
F
Wang
Yan
Y
Golas
Jennifer M
JM
Lucas
Judy
J
Boschelli
Frank
F
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors; D051379:Mice; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011804:Quinolines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D016315:Proto-Oncogene Proteins c-abl; D016392:Proto-Oncogene Proteins pp60(c-src)