Potent and selective inhibitors of PDGF receptor phosphorylation. 2. Synthesis, structure activity relationship, improvement of aqueous solubility, and biological effects of 4-[4-(N-substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives.
4-[4-(N-Substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives such as KN1022 are potent inhibitors of the phosphorylation of platelet derived growth factor receptor (PDGFR). Structure activity relationships in the (thio)urea moiety, the phenyl ring itself, the linker between these two moieties, and the piperazine moiety were investigated. The role of the linker was found to be quite different, where ureas yielded decreasing activity, while thioureas provided increasing activity. Cyanoguanidine as a bioisostere of thiourea and related dicyanovinyl or nitrovinyl groups were not suitable for potent activity. A hydrogen atom on the (thio)urea moiety was essential for activity. Stereochemistry was also important for inhibition of PDGFR phosphorylation. Through the modification of these moieties, benzylthiourea analogues with a small substituent on the 4-position and the 3,4-methylenedioxy group (KN734/CT52923) were found to be optimal for selective and potent activity. Replacement of the phenyl ring by heterocycles improved aqueous solubility without loss of activity and kinase selectivity. Introduction of a methyl group on 5-position of the piperazine ring and replacement by homopiperazine reduced inhibitory activity. An efficient synthetic method was also developed for 2-pyridylurea-containing analogues, via carbonylation of 2-aminopyridine with N,N'-carbonyldiimidazole. A potent analogue, KN734, inhibited smooth muscle cell proliferation and migration induced by platelet derived growth factor-BB (PDGF-BB) and suppressed neointima formation following balloon injury in rat carotid artery by oral administration. Therefore, 4-[4-(N-substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.
Matsuno
Kenji
K
Kyowa Hakko Kogyo Co., Ltd., Pharmaceutical Research Institute, Shimotogari 1188, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan. kenji.matsuno@kyowa.co.jp
Nakajima
Takao
T
Ichimura
Michio
M
Giese
Neill A
NA
Yu
Jin-Chen
JC
Lokker
Nathalie A
NA
Ushiki
Junko
J
Ide
Shin-ichi
S
Oda
Shoji
S
Nomoto
Yuji
Y
D000284:Administration, Oral; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects; D066298:In Vitro Techniques; D010766:Phosphorylation; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D012995:Solubility; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects; D014867:Water
D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013859:Thiocarbamates; D014867:Water; D020797:Receptor, Platelet-Derived Growth Factor beta