Identification of potent and selective inhibitors of PDGF receptor autophosphorylation.
We report the structure-activity relationship of quinoline and quinazoline derivatives, which include urea, thiourea, urethane, and acylthiourea groups, as inhibitors of the platelet-derived growth factor (PDGF) receptor autophosphorylation. Our previous studies showed that the quinoline and quinazoline derivatives including urea, thiourea, and carbamate groups were highly potent compounds as the PDGF receptor autophosphorylation inhibitor, but these compounds did not exhibit receptor selectivity between the PDGF receptor and the c-kit receptor. As a result of further synthesis and biological evaluation, we have found that the quinoline and quinazoline-acylthiourea derivatives showed not only good inhibitory activity for the PDGF receptor but also receptor selectivity between the PDGF receptor and the c-kit receptor. Furthermore N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(2-methylbenzoyl)thiourea exhibited potent oral efficacy in in vivo assay using the rat carotid balloon injury model. Therefore, the quinoline and quinazoline-acylthiourea derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.
Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd., 3 Miyahara, Takasaki, Gunma 370-1295, Japan. t-furuta@kirin.co.jp
Takayuki
T
Furuta
Teruyuki
T
Sakai
Terufumi
T
Senga
Tatsushi
T
Osawa
Kazuo
K
Kubo
Toshiyuki
T
Shimizu
Rika
R
Suzuki
Tetsuya
T
Yoshino
Megumi
M
Endo
Atsushi
A
Miwa
D000284:Administration, Oral; D000818:Animals; D016893:Carotid Stenosis / Q000517:prevention & control; D002460:Cell Line; D008297:Male; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
C509924:N-(4-((6,7-dimethoxy-4-quinolyl)oxy)phenyl)-N'-(2-methylbenzoyl)thiourea; D011799:Quinazolines; D011804:Quinolines; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D013890:Thiourea