Research and development of cilostazol: An antiplatelet agent

In our study, we focused on the fact that platelets play a significant role in thrombus formation in the arterial vessels, and started exploratory research on the antiplatelet agent with a vasodilating action in order to discover a more effective drug for arterial thrombosis. We synthesized many 2(1H)-quinolinone derivatives and evaluated their inhibition of platelet aggregation and their vasodilating activities. First we found cilostamide, which has an amide moiety in the side chain. This compound possessed desired activities, but it caused a side effect of tachycardia, and so, unfortunately, we were unable to pursue its development. After many efforts to modify the side chain moiety to eliminate this side effect, we finally invented cilostazol (OPC-13013), a 2(1H)-quinolinone derivative with a tetrazol ring in the side chain. Cilostazol inhibited human platelet aggregation induced by various stimuli including shear stress in vitro and showed potent antiplatelet effects both in vitro and ex vivo. It was also shown that the drug has antithrombotic effects in experimental thrombus models and a vasodilating activity of the femoral artery and vertebral artery. The mechanism of the action for cilostazol is specific inhibition of cyclic nucleotide phosphodiesterase type 3 (PDE3). Cilostazol was marketed first in Japan in 1988 and later in seven other countries for the treatment of chronic arterial occlusion. It was launched in the U.S. in 1999, and approved in United Kingdom for the treatment of intermittent claudication. More recently, cilostazol was shown to be effective in a clinical prevention study on recurrence of cerebral infarction, and has been applied to the approval of the indication in Japan.