1. Design, Synthesis, and Biological Evaluation of Peptidomimetic Inhibitors of Factor XIa as Novel Anticoagulants
- Author
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Lei Jin, Thomas D. Bannister, Frank Bibbins, Susan M. Cantin, Jesse Quinn, Pamela Nagafuji, James E. Strickler, Robert E. Babine, Neil J Hayward, Jian Lin, David R. Weaver, Harold V Meyers, Cassandra Celatka, Sherin S. Abdel-Meguid, Pramod Pandey, Howard Benjamin, Hongfeng Deng, Joan C. Gorga, Michael J. Rynkiewicz, and Frans L Stassen
- Subjects
Male ,Serine Proteinase Inhibitors ,medicine.drug_mechanism_of_action ,Protein Conformation ,Peptidomimetic ,Factor Xa Inhibitor ,Crystallography, X-Ray ,Factor XIa ,Rats, Sprague-Dawley ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Thrombin ,Drug Discovery ,Antithrombotic ,medicine ,Animals ,Humans ,Structure–activity relationship ,Venous Thrombosis ,Serine protease ,Binding Sites ,Molecular Structure ,biology ,medicine.diagnostic_test ,Chemistry ,Anticoagulants ,Peptide Fragments ,Rats ,Biochemistry ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine ,Partial Thromboplastin Time ,Factor Xa Inhibitors ,Protein Binding ,Partial thromboplastin time ,medicine.drug - 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 with1000-fold FXa selectivity and100-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.
- Published
- 2006