The Design of Competitive, Small-molecule Inhibitors of Coagulation Factor Xa

The last five years has seen an explosion of research into inhibitors of Factor Xa as potential antithrombotic agents. Aventis Pharma through its founder company Rhone-Poulenc Rorer was a participant in this effort and contributed significantly to the discovery of new inhibitors in recent years. This chapter traces the systematic development of the former Rhone-Poulenc Rorer factor Xa program from conception to the realization of potent, orally bioavailable inhibitors with exquisite selectivity against other serine proteases. The work on β- aminoesters described in Part 1 culminates in the development of FXV673 (Ki = 0.5 nM), an effective anticoagulant for acute indications. Part 2.2 details the de novo design of a pyrrolidinone series of inhibitors, within which a group of efficacious i.v. agents were identified (e.g RPR130737, Ki = 2 nM). The first active and bioavailable benzamidine isostere i.e. the 1-aminoisoquinoline (RPR208815, Ki = 22 nM) was discovered on the pyrrolidinone scaffold (Part 2.3). Ultimately a variety of benzamidine mimics were explored and incorporated into the ketopiperazine series (Part 3); the 6-substituted aminoquinazolines were found to be subnanomolar against factor Xa and highly selective. The azaindole moiety stands out as imparting favorable pharmacokinetic properties to the sulfonamido-ketopiperazines; RPR209685, a potent representative (Ki = 1 nM), was shown to be orally efficacious in the dog.