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1.
J Cardiovasc Pharmacol ; 42(6): 745-51, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14639096

ABSTRACT

The dedifferentiation of vascular smooth muscle cells (VSMCs) plays a critical role in the progression of atherosclerosis and restenosis after angioplasty. Thus, factors that stimulate smooth muscle cell differentiation should be useful for therapy for these diseases. Previously, we found that l-ascorbic acid (L-Asc) induces the expression of smooth muscle-specific genes in a pluripotent bone marrow stromal cell line, TBR-B. This finding suggests that l-Asc stimulates the differentiation of smooth muscle cells. In the present study, we investigated the effects of l-Asc and its derivatives on the differentiation state of VSMCs in vitro and in vivo. l-Asc and its long-lasting derivatives stimulated the production of smooth muscle-specific myosin heavy chain-1 (SM1) and calponin 1 in a dose-dependent manner in rat cultured VSMCs, and the elevated production of SM1 and calponin 1 was maintained for at least 2 weeks. Moreover, oral administration of 3 g/kg of l-Asc to the balloon-injured rats induced a higher expression of SM1 and calponin 1 in the injured arteries compared with that from administration of the delivery vehicle alone. These data demonstrated new biologic activity, such as the stimulation of VSMC differentiation, of l-Asc and its long-lasting derivatives. In addition, these compounds may serve as useful tools for analysis of the differentiation of VSMCs and for therapy for vascular diseases.


Subject(s)
Antioxidants/pharmacology , Ascorbic Acid/pharmacology , Calcium-Binding Proteins/biosynthesis , Muscle, Smooth, Vascular/drug effects , Myosin Heavy Chains/biosynthesis , Animals , Ascorbic Acid/analogs & derivatives , Carotid Arteries/drug effects , Carotid Arteries/metabolism , Cells, Cultured , Male , Microfilament Proteins , Muscle, Smooth, Vascular/metabolism , Rats , Rats, Sprague-Dawley , Rats, Wistar , Calponins
2.
J Med Chem ; 45(14): 3057-66, 2002 Jul 04.
Article in English | MEDLINE | ID: mdl-12086491

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.


Subject(s)
Quinazolines/chemical synthesis , Receptor, Platelet-Derived Growth Factor beta/metabolism , Administration, Oral , Animals , Becaplermin , Carotid Artery Diseases/drug therapy , Carotid Artery Diseases/etiology , Carotid Artery Diseases/pathology , Catheterization/adverse effects , Cell Division/drug effects , Depression, Chemical , Male , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Phosphorylation , Phosphotransferases/metabolism , Platelet-Derived Growth Factor/pharmacology , Proto-Oncogene Proteins c-sis , Quinazolines/chemistry , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Swine , Tunica Intima/drug effects , Tunica Intima/pathology
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