title: Potent and selective inhibitors of platelet-derived growth factor receptor phosphorylation. 1. Synthesis, structure-activity relationship, and biological effects of a new class of quinazoline derivatives.
abstract: A new series of 4-[4-(N-substituted carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives were found to show potent and selective inhibition of platelet-dervied growth factor (PDGF) receptor phosphorylation. In this exploration of the structure-activity relationships (SARs) of the prototype inhibitor KN1022, the 4-nitrophenylurea moiety was probed. We found that 4-substitution on the phenyl ring was optimal and the introduction of more than two substituents on the phenyl ring decreased activities. Bulky substituents on the phenyl ring enhanced activities. Thiourea analogues were also prepared, and the SARs were found to be slightly different from those of the urea derivatives. Through this research, we obtained some potent KN1022 derivatives such as 4-(4-methylphenoxy)phenyl (36, IC(50) 0.02 micromol/L), 4-tert-butylphenyl (16, IC(50) 0.03 micromol/L), and 4-phenoxyphenyl (21, IC(50) 0.08 micromol/L) analogues, which had almost a 10-fold increase in activity against KN1022. These potent compounds retained their high selectivity against the PDGF receptor family similar to KN1022. We also observed that these compounds could inhibit the PDGF-BB-induced proliferation of porcine vascular smooth muscle cells without cell toxicity almost at the same IC(50) values observed for PDGF receptor phosphorylation. To evaluate the biological effects in vivo, we selected some analogues on the basis of the measurement of the plasma drug concentration after oral administration to rats. Oral administration of the 4-chlorophenyl (6), 4-bromophenyl (9), or 4-isopropoxyphenyl (20) analogue to Sprague-Dawley rats (30 mg/kg, twice daily) resulted in significant inhibition (24-38%) of neointima formation in the carotid artery of the balloon catheter deendothelialized vessel in the rats. Therefore, 4-[4-(N-substituted carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives, which are potent inhibitors of PDGFR phosphorylation, may be expected to represent a new therapeutic approach for the treatment of various aspects of atherosclerosis and other cellular proliferative disorders.
authors.affiliation: Pharmaceutical Research Institute, Kyowa Hakko Kogyo Company, Ltd., Shimotogari 1188, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsuno
authors.forename: Michio
authors.initials: M
authors.lastname: Ichimura
authors.forename: Takao
authors.initials: T
authors.lastname: Nakajima
authors.forename: Keiko
authors.initials: K
authors.lastname: Tahara
authors.forename: Shigeki
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kase
authors.forename: Junko
authors.initials: J
authors.lastname: Ushiki
authors.forename: Neill A
authors.initials: NA
authors.lastname: Giese
authors.forename: Anjali
authors.initials: A
authors.lastname: Pandey
authors.forename: Robert M
authors.initials: RM
authors.lastname: Scarborough
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Lokker
authors.forename: Jin-Chen
authors.initials: JC
authors.lastname: Yu
authors.forename: Junko
authors.initials: J
authors.lastname: Irie
authors.forename: Eiji
authors.initials: E
authors.lastname: Tsukuda
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ide
authors.forename: Shoji
authors.initials: S
authors.lastname: Oda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nomoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000077214:Becaplermin; D002340:Carotid Artery Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects; D002455:Cell Division / Q000187:drug effects; D003864:Depression, Chemical; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
chemical_list: D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011799:Quinazolines; D000077214:Becaplermin; D010770:Phosphotransferases; D020797:Receptor, Platelet-Derived Growth Factor beta