Novel factor Xa inhibitors: a patent review.
BACKGROUND
New oral anticoagulants with favorable safety profiles and fixed doses are required for the management of thromboembolism and stroke prevention in patients with atrial fibrillation. Among them, fXa inhibitors (the so-called xabans) are attractive options that can overcome limitations (e.g., bleeding) of the current oral antithrombotic therapy. The rational design of small-molecule direct fXa inhibitors, whose importance is testified by the growing number of publications and patents recently registered, has been fully supported by the X-ray crystallography of enzyme-ligand complexes.


METHODS
Pubmed, SciFinder Scholar, ISI web of knowledge(SM), http://ep.espacenet.com/ and Google websites were used as the main sources for literature retrieving, and > 100 patents filed between 2006 and April 2009, reviewed and discussed herein, highlight the variety among the P1 and P4 moieties on suitable scaffolds.


RESULTS
The replacement of the benzamidine P1 moiety, which characterizes the first generation, with less basic bioisosteric or nonpolar neutral P1 groups led to the disclosure of numerous fXa inhibitors with high potency, selectivity and oral bioavailability. Novel selective fXa inhibitors with stable pharmacokinetics, better therapeutic windows and ease-of-use than the existing anticoagulants are currently under advanced stage clinical trials.


CONCLUSIONS
Available data from Phase II and Phase III studies reflect the drive towards fXa inhibitors as potentially more effective and safer antithrombotic drugs. Their development is expected to address two major needs for anticoagulation, namely safety and ease-of-use, and to significantly affect the anticoagulant market.
de Candia
Modesto
M
University of Bari, Dipartimento Farmaco-Chimico, Via E. Orabona 4, I-70125 Bari, Italy.
Lopopolo
Gianfranco
G
Altomare
Cosimo
C
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D010330:Patents as Topic; D020521:Stroke / Q000209:etiology / Q000517:prevention & control; D013923:Thromboembolism / Q000188:drug therapy
D000925:Anticoagulants; D065427:Factor Xa Inhibitors