Synthesis of Potent and Selective Inhibitors against the Proliferation of Human Coronary Artery Smooth Muscle Cells.

Abstract

Proliferation of smooth muscle cells (SMCs) plays an important role in restenosis and in progression of atherosclerosis.2) Tranilast has been shown to inhibit platelet-derived growth factor (PDGF)-induced migration and proliferation in both SMCs 3) and endothelial cells (ECs). And the multicenter, randomized, double-blinded placebo-controlled trials demonstrated the potent preventive effect on restenosis after percutaneous transluminal coronary angioplasty (PTCA) in Japanese patients. 4,5) [at the phase III trial, 5) restenosis rate 18.8% (Tranilast 600 mg/d for 3 months, nϭ112) versus 44.1% (placebo, nϭ127); pϭ0.00005] But some patients had suffered liver dysfunction in these trials. We speculated that these frequent and severe side effects in these trials might have been caused by the high dose of Tranilast. In addition, the selective inhibitors of the proliferation of SMCs over that of ECs was more preferable for the treatment of restenosis than the non-selective inhibitors like Tranilast.6) So, we had been trying to search more potent and SMCs-selective compounds by modification of Tranilast.We previously reported a series of diarylamide derivatives, exhibiting potent and highly selective inhibition against SMCs proliferation induced by PDGF-BB. 7) We conducted that structure-activity relationship (SAR) study of the substituents at the A and B rings, and found potent inhibitor, 1a, which had about 30-fold stronger activity than Tranilast. In that case, the linker between A and B rings was not so influenced on the inhibitory activities (1a-c). In order to find more potent inhibitor, we also reported that the introduction of a ureido group to the B ring of our diarylamide derivatives make the inhibitory activity more potent and keep the selectivity for SMCs and 2b showed the most potent inhibitory activity for SMCs (IC 50 = 40 nM), which was 20-and 600-fold stronger than 1a and Tranilast respectively. 8) On the basis of these results (Fig. 1), we tried to confirm the effect of the linker between these rings against the proliferation of SMCs. In this paper, we report the results of the further modification of these urea derivatives. ChemistryThe syntheses of desired urea derivatives 2c-s are outlined in Chart 1. The condensation of 3 8) with corresponding acid halides was performed in the presence of triethylamine to provide 4a-c. Acid halide 10 was prepared from 9 with thionyl chloride, which was obtained by the condensation of 8 with ethyl bromoacetate followed by basic hydrolysis. Then, catalytic hydrogenation, followed by the condensation of 5a-c with the corresponding isocyanates gave the desired urea derivatives 2c-s. Compound 2e was obtained by the condensation of 3 with 7 by using 2-chloro-1,3-dimethylimidazolidium hexafluorophosphate (CIP) 9,10) as a condensation reagent. BiologyA series of these compounds were evaluated for their inhibitory activities on PDGF-induced proliferation of human coronary artery SMCs and fetal bovine serum (FBS)-induced the proliferation of human coronary artery ECs. Inhibit...