Discovery of a Novel, Potent, and Specific Family of Factor Xa Inhibitors via Combinatorial Chemistry

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Abstract
A series of low molecular weight peptide inhibitors of factor Xa, unrelated to any previously described, was identified by screening a combinatorial peptide library composed of l-amino acids. The minimal inhibitory sequence is a tripeptide, l-tyrosinyl-l-isoleucyl-l-arginyl, which competitively inhibits the hydrolysis of small chromogenic substrates by factor Xa but binds in an orientation which prevents a productive nucleophilic attack by serine 195 of the catalytic triad on the carbonyl carbon of the carboxy-terminal arginine. The initial leads identified in an octamer combinatorial peptide library ranged in potency from 4 to 15 μM. These peptides were modified into peptide mimetics with a greater than 1000-fold increase in potency while retaining unusual selectivity for factor Xa over the related serine proteases thrombin, factor VIIa/tissue factor, plasmin, activated protein C, kallikrein, and trypsin. One of the most potent analogues, SEL 2711, with a Ki of 0.003 μM for factor Xa and 40 μM for thrombin, is active in in vitro and ex vivo coagulation assays, suggesting the potential application of these inhibitors in anticoagulant therapy.