Design, Synthesis and Biological Evaluation of Thrombin Inhibitors with 1,2,3,4-Tetrahydrobenzo [4,5] imidazo [1,2-a] pyrazine Nucleus

作者：Chen Dongxing; Shi Jinyu; Chen Qiufang; Zhang Rui; Gong Guoqing; Xu Yungen^*; Zhu Qihua^*

来源：Chemical Journal of Chinese Universities, 2017, 38(6): 1059-1067.

DOI：10.7503/cjcu20160797

• Benzimidazole
• Thrombin inhibitors
• Antithrombosis

Compound 1, a new thrombin inhibitor with 1,2,3,4-tetrahydrobenzo [4,5] imidazo [1,2-a] pyrazine nucleus, was selected as lead compound, and fourteen carbamate derivatives derivatives(2a-6a, 2b-6b, 7-10) were designed and prepared. Furthermore, a twin drug(11) was synthesized by coupling compound 1 with 2-hydroxymethyl. 3, 5, 6. trimethylpyrazine (HTMP). The structures of all the target compounds were confirmed by H-1 NMR, C-13 NMR and HRMS. Preliminary biological activity test results indicated that all of the tested compounds exhibit a certain degree of inhibitory effect on thrombin. induced platelet aggregation, among which compound 4b [IC50 =(0.11 +/- 0.08) mu mol/L] show better anti. platelet aggregation activity than dabigatran etexilate [IC50 =(0.60 +/- 0.05) mu mol/L]. The in vivo experimental results in rat venous thrombosis model demonstrated compound 4b can significantly reduce thrombosis in a dose. response manner. Compound 11, which showed weak inhibitory effect on thrombin. induced platelet aggregation, also displayed comparable inhibitory effect on rat venous thrombosis with dabigatran etexilate. The study points out that the enhanced potency of compound 11 may be the synergetic effect of HTMP and compound 1 which are generated by hydrolysis in vivo.

• 出版日期2017-6-10
• 单位中国药科大学