title: Synthesis and structure-activity relationship for new series of 4-phenoxyquinoline derivatives as specific inhibitors of platelet-derived growth factor receptor tyrosine kinase.
abstract: We discovered a new series of 4-phenoxyquinoline derivatives as potent and selective inhibitors of the platelet-derived growth factor receptor (PDGFr) tyrosine kinase. We researched the highly potent and selective inhibitors on the basis of both PDGFr and epidermal growth factor receptor (EGFr) inhibitory activity. First, we found a compound, Ki6783 (1), which inhibited PDGFr autophosphorylation at 0.13 microM, but it did not inhibit EGFr autophosphorylation at 100 microM. After extensive explorations, we found the two desired compounds, Ki6896 (2) and Ki6945 (3), which are substituted by benzoyl and benzamide at the 4-position of the phenoxy group on 4-phenoxyquinoline, respectively. These inhibitory activities were 0.31 and 0.050 microM, respectively, but neither of them inhibited EGFr autophosphorylation at 100 microM. We further investigated the profile of both compounds toward various tyrosine and serine/threonine kinases. The three compounds specifically inhibited PDGFr rather than the other kinases.
authors: Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd., 3Miyahara-cho, Takasaki-shi, Gunma, 370-1295, Japan. ka-kubo@kirin.co.jp
authors: Kazuo
authors: K
authors: Kubo
authors: Shin-ichi
authors: S
authors: Ohyama
authors: Toshiyuki
authors: T
authors: Shimizu
authors: Atsuya
authors: A
authors: Takami
authors: Hideko
authors: H
authors: Murooka
authors: Tsuyoshi
authors: T
authors: Nishitoba
authors: Shinichiro
authors: S
authors: Kato
authors: Mikio
authors: M
authors: Yagi
authors: Yoshiko
authors: Y
authors: Kobayashi
authors: Noriko
authors: N
authors: Iinuma
authors: Toshiyuki
authors: T
authors: Isoe
authors: Kazuhide
authors: K
authors: Nakamura
authors: Hiroshi
authors: H
authors: Iijima
authors: Tatsushi
authors: T
authors: Osawa
authors: Toshio
authors: T
authors: Izawa
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D041681:NIH 3T3 Cells; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011804:Quinolines; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor