title: Orally active anti-proliferation agents: novel diphenylamine derivatives as FGF-R2 autophosphorylation inhibitors.
abstract: (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.
authors.affiliation: Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd., 3 Miyahara, Takasaki, Gunma, 370-1295, Japan. tshimuzu@kirin.co.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Shimizu
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Osawa
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Sakai
authors.forename: Kinya
authors.initials: K
authors.lastname: Kubo
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kubo
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nishitoba
authors.forename: Kaname
authors.initials: K
authors.lastname: Kimura
authors.forename: Terufumi
authors.initials: T
authors.lastname: Senga
authors.forename: Hideko
authors.initials: H
authors.lastname: Murooka
authors.forename: Akemi
authors.initials: A
authors.lastname: Iwai
authors.forename: Kayoko
authors.initials: K
authors.lastname: Fukushima
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yoshino
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miwa
mesh_terms: 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
chemical_list: 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