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
| Autor: | Neill A. Giese, Anjali Pandey, Eiji Tsukuda, Junko Irie, Nathalie Lokker, Michio Ichimura, Yuji Nomoto, Takao Nakajima, Keiko Tahara, Kenji Matsuno, Junko Ushiki, Shoji Oda, Jin-Chen Yu, Robert M. Scarborough, Shigeki Fujiwara, Hiroshi Kase, Shinichi Ide |
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| Rok vydání: | 2002 |
| Předmět: |
Carotid Artery Diseases
Male Platelet-derived growth factor Stereochemistry Swine medicine.medical_treatment Becaplermin Administration Oral Muscle Smooth Vascular Catheterization Rats Sprague-Dawley Receptor Platelet-Derived Growth Factor beta chemistry.chemical_compound Structure-Activity Relationship In vivo Drug Discovery medicine Structure–activity relationship Animals Phosphorylation Platelet-Derived Growth Factor biology Growth factor Phosphotransferases Balloon catheter Proto-Oncogene Proteins c-sis Rats chemistry Enzyme inhibitor Depression Chemical biology.protein Quinazolines Molecular Medicine Tunica Intima Platelet-derived growth factor receptor Cell Division |
| Zdroj: | Journal of medicinal chemistry. 45(14) |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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