Details

Autor(en) / Beteiligte

• Chen, Dongxing
• Shi, Jinyu
• Liu, Jing
• Zhang, Xueying
• Deng, Xiaoying
• Yang, Yanyan
• Cui, Shuang
• Zhu, Qihua
• Gong, Guoqing
• Xu, Yungen

Titel

Design, synthesis and antithrombotic evaluation of novel non-peptide thrombin inhibitors

Ist Teil von

• Bioorganic & medicinal chemistry, 2017-01, Vol.25 (2), p.458-470

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• Design of the target compounds. [Display omitted] Ten derivatives of 4-((1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-1-yl)methyl)benzimida-mide (I-1∼I-2, II-1∼II-8) were designed, synthesized and evaluated for their inhibitory effect on human thrombin. Compound II-7 (IC50=82.8nM), which showed the strongest thrombin inhibitory activity among the tested compounds, was chosen as the lead compound, and ten carbamate derivatives (II-9a∼II-13a, II-9b∼II-12b, II-14) were prepared and evaluated for their anticoagulant activity. The results indicate that most of the tested compounds exhibit a certain degree of inhibitory effect on thrombin-induced platelet aggregation, among which compounds II-11a (IC50=8.16μM) and II-14 (IC50=1.95μM) show better anti-platelet aggregation activity than the others. The in vivo experimental results in rat venous thrombosis model also demonstrate compounds II-11a and II-14 can significantly reduce thrombosis in a dose-response manner. It is worth pointing out that the enhanced potency of compound II-14 may be the synergetic effect of 2-hydroxymethyl-3,5,6-trimethylpyrazine (HTMP) and II-7 which are generated by hydrolysis in vivo.