Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants |
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Authors: | Lin Jian Deng Hongfeng Jin Lei Pandey Pramod Quinn Jesse Cantin Susan Rynkiewicz Michael J Gorga Joan C Bibbins Frank Celatka Cassandra A Nagafuji Pamela Bannister Thomas D Meyers Harold V Babine Robert E Hayward Neil J Weaver David Benjamin Howard Stassen Frans Abdel-Meguid Sherin S Strickler James E |
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Affiliation: | Daiichi Asubio Medical Research Laboratories LLC (DAIAMED), One Kendall Square Building 700, Cambridge, MA 02139, USA. jlin@epixpharma.com |
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Abstract: | Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, 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, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar 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 microM and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy. |
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