Orally active anti-proliferation agents: novel diphenylamine derivatives as FGF-R2 autophosphorylation inhibitors.
(6,7-Disubstituted-quinolin-4-yloxy-phenyl)(4-substituted-phenyl)amine derivatives were synthesized and evaluated by a cellular autophosphorylation assay for FGF-R2 in the human scirrhous gastric carcinoma cell line, OCUM-2MD3. We also performed metabolic stability studies showing that substitutions at the 7-position of quinoline affect its biological stability. In this study, we achieved a remarkable improvement in the solubility and metabolic stability of the diphenylamine derivative. The most promising compound 15e showed a significant decrease in tumor volume when orally administered.
Shimizu
Toshiyuki
T
Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd., 3 Miyahara, Takasaki, Gunma, 370-1295, Japan. tshimuzu@kirin.co.jp
Fujiwara
Yasunari
Y
Osawa
Tatsushi
T
Sakai
Teruyuki
T
Kubo
Kinya
K
Kubo
Kazuo
K
Nishitoba
Tsuyoshi
T
Kimura
Kaname
K
Senga
Terufumi
T
Murooka
Hideko
H
Iwai
Akemi
A
Fukushima
Kayoko
K
Yoshino
Tetsuya
T
Miwa
Atsushi
A
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D010766:Phosphorylation; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D013274:Stomach Neoplasms / Q000188:drug therapy
D000970:Antineoplastic Agents; D017468:Receptors, Fibroblast Growth Factor; D004159:Diphenylamine; C496353:FGFR2 protein, human; C496356:Fgfr2 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2