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

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• 作者：Dongxing Chen^a ; ^d ; Jinyu Shi^b ; ^d ; Jing Liu^b ; Xueying Zhang^b ; Xiaoying Deng^b ; Yanyan Yang^b ; Shuang Cui^c ; Qihua Zhu^b ; ; Guoqing Gong^c ; Yungen Xu^a ; ^b ; ^{xu_yungen@hotmail.com}
• 关键词：PHRVUKVPNAEALL-UHFFFAOYSA-N ; ILVLGGOEARRHPX-UHFFFAOYSA-N ; GWQOWRLVXRXXGY-UHFFFAOYSA-N ; LGVDAFBCFAMLNA-UHFFFAOYSA-N ; JQELBHGAZYOILL-UHFFFAOYSA-N ; IBSQBEOEOJNXDG-UHFFFAOYSA-N ; RJAOUGLYTLQSDK-UHFFFAOYSA-N ; NWNBPVXRRRWIAN-UHFFFAOYSA-N ; ANXQNEANKKIVCR-UHFFFAOYSA-N ; SKHSFQDFSNIGLL-UHFFFAOYSA-N ; VFJJVYVHWTWNPY-UHFFFAOYSA-N ; XLEQJOHUTWJBQQ-UHFFFAOYSA-N ; JQKFRDMILWKLSS-UHFFFAOYSA-N ; UTRHHFYSMSXJRH-UHFFFAOYSA-N ; IQOBXOFWCZUJLD-UHFFFAOYSA-N ; QMUFQBIQMQJUED-UHFFFAOYSA-N ; ZYCXYTNQQMOFHW-UHFFFAOYSA-N ; SPPPFIZ
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：25
• 期：2
• 页码：458-470
• 全文大小：2024 K
• 卷排序：25

文摘

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 = 82.8 nM), 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 = 8.16 μM) and II-14 (IC50 = 1.95 μM) 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.