Synthesis and structure-activity relationship for new series of 4-phenoxyquinoline derivatives as specific inhibitors of platelet-derived growth factor receptor tyrosine kinase |
| |
Authors: | Kubo Kazuo Ohyama Shin-ichi Shimizu Toshiyuki Takami Atsuya Murooka Hideko Nishitoba Tsuyoshi Kato Shinichiro Yagi Mikio Kobayashi Yoshiko Iinuma Noriko Isoe Toshiyuki Nakamura Kazuhide Iijima Hiroshi Osawa Tatsushi Izawa Toshio |
| |
Institution: | Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd., 3Miyahara-cho, Takasaki-shi, Gunma, 370-1295, Japan. ka-kubo@kirin.co.jp |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|