PMID: 11899252Mar 20, 2002Paper

The design of competitive, small-molecule inhibitors of coagulation factor Xa

Current Topics in Medicinal Chemistry
H W Pauls, W R Ewing

Abstract

The last five years have seen an explosion of research into inhibitors of Factor Xa as potential antithrombotic agents. Aventis Pharma was a participant in this effort and its two founder companies have substantially contributed to the discovery of new inhibitors over the years. This review 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 beta-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 the pyrrolidinone series of inhibitors (RPR120844), 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; the 6-substituted aminoquinazolines were found to be the most potent (Part 3). The azaindole, as represented by RPR200443 (K...Continue Reading

Citations

Jan 27, 2004·The Annals of Pharmacotherapy·Edith A Nutescu, Ann K Wittkowsky
Apr 18, 2002·Bioorganic & Medicinal Chemistry Letters·Wei HeValeria Chu
Dec 14, 2007·Bioorganic & Medicinal Chemistry·Yasuhiro ImaedaKeiji Kubo
Sep 6, 2002·Nature·Edward Tuddenham
Jun 27, 2012·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Elena I SinauridzeFazoil I Ataullakhanov
Jul 9, 2003·Cardiovascular Drug Reviews·Brigitte Kaiser
Mar 17, 2006·Journal of Medicinal Chemistry·Dora M SchnurAndrew J Tebben
May 30, 2008·Journal of Medicinal Chemistry·Yasuhiro ImaedaKeiji Kubo
May 28, 2010·Journal of Medicinal Chemistry·Donald J P PintoRuth R Wexler
Feb 21, 2003·Journal of Medicinal Chemistry·Yong Mi Choi-SledeskiVincent Mikol

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