The Design, Synthesis And Activity Of F16618 Analogs

Thrombotic disease is a common clinical cardiovascular disease because of the highest incidence of various diseases, it has become an important health issue that humanity facing today. Currently antithrombotic drugs include Aspirin and Plavix, but they have limited efficacy and adverse reaction of bleeding, which greatly limits the scope of application of the drugs. In the last century 90’s, Professor Coughlin’s team found and cloned the thrombin receptor of platelet in the America, which provided a new target for the study of antithrombotic drugs. Thrombin receptor antagonist can selectively inhibit the activation of the platelet mediated by thrombin, prevent thrombosis without affecting the normal hemostasis of human body, it is an ideal antithrombotic drug.F16618 is a new type of simple and small molecule PAR-1 antagonist developed by the Fabre Pierre research center in France, which has a good antithrombotic activity in vitro and in vivo and no increase of bleeding. Therefore, F16618 may have better properties than previous drugs with good development prospects. We have designed and synthesized a series of new structures, which are based on our earlier research on F16618 analogues which modified the not ideal group of its structure, and testing of the antiplatelet activity. The structures of these compounds are similar to F16618, the synthesis route is simple, and it is expected to reduce side effect and retain the biological activity of F16618.We use simple, efficient, environmentally friendly and economical modern organic synthesis method to synthesize these new compounds. A total of 44 compounds were obtained. It not only verifid the feasibility of the synthesis method, but also laid a solid foundation for the further research. The synthesized compounds were separated and purified by thin layer chromatography and flash chromatography and recrystallization.The purity and structure were determined by liquid chromatography-mass spectrometry and nuclear magnetic resonance.Cooperating with HD Bioscience Co. Ltd. in Shanghai and Eurofins Cerep SAcompany in France, using the activity data of F16618 and QTU-003 as the reference, we chose a more suitable and more accurate method to determine the biological activity in vitro of these 44 compounds. The structure activity relationship of each compound was obtained and the structural characteristics of the active compounds were also revealed.The results showed that QTU-114, QTU-118 had same or better biological activity than the compounds F16618. Their structure is simple and stable, the synthetic route is practical and the yield is high which provide a rich data base for the further research of PAR-1 antagonists.