The Design, Synthesis And Activity Studis Of Novel Thrombin Receptor Antagonists As Antithrombotics

Thrombotic disease is a serious threat to human health, mainly by pathologicalcoagulation it caused. The current antithrombotic treatments include Aspirin and Plavix.However, their therapeutic applications are limited by their moderate efficacy andbleeding side effects. The discovery of the thrombin receptor provided a new target fornovel antithrombotic drug discovery. A couple of novel thrombin receptor antagonists,such as Vorapaxar, E5555, F16618, etc., have been reported and have good efficacy ininhibiting the thrombin receptor. They bring hope and direction for the development ofnovel thrombin receptor antagonists.The goal of this study is to discover novel thrombin receptor antagonists based onthe compound F16618that will have good efficacy. By designing and synthesizing thesecompounds and studying the structure and activity relationships, we aim to discoverstructural features that will lead to good efficacy.Based on the compound F16618and replacing its unsaturated double bond with abenzene ring, we designed a series of novel compounds which have a biphenyl scaffold.Then, we obtained32new compounds by chemical synthesis for biological studies. Bythe methods of HPLC,1H NMR, LC-MS, we analyzed and confirmed the identity ofthese new compounds.To study the biological activity of these new compounds, we collaborated with HDBioscience Co. Ltd., Shanghai, to screen these new compounds in vitro. The screeningresults showed that the compound QTU-038,85and86were equally active ascompound F16618, which is encouraging for further study of structure optimizations ofthese thrombin receptor antagonists.