Design, Synthesis, and Biological Evaluation of Peptidomimetic Inhibitors of Factor XIa as Novel Anticoagulants

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• 作者：Jian Lin ; Hongfeng Deng ; Lei Jin ; Pramod Pandey ; Jesse Quinn ; Susan Cantin ; Michael J. Rynkiewicz ; Joan C. Gorga ; Frank Bibbins ; Cassandra A. Celatka ; Pamela Nagafuji ; Thomas D. Bannister ; Harold V. M
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：December 28, 2006
• 年：2006
• 卷：49
• 期：26
• 页码：7781 - 7791
• 全文大小：376K
• 年卷期：v.49,no.26(December 28, 2006)
• ISSN：1520-4804

文摘

Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI bythrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade.To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selectivepeptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed lownanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and >100-fold thrombin selectivity.The X-ray structure of one of these inhibitors, 36, demonstrates its unique binding interactions with FXIa.Compound 32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4 Mand was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significantrole in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.