Novel inhibitors of factor X for use in cardiovascular diseases.
The complementary roles of platelets and thrombin in the pathophysiology of acute coronary syndromes suggests that for treatment to be effective, both mediators must be targeted. Although great strides have been made in the development of antiplatelet therapies, attempts to inhibit thrombin have been less successful. Unfractionated heparin is limited by a number of pharmacologic shortcomings as well as an inability to meaningfully suppress thrombin generation. The low molecular weight heparins have yielded encouraging results in large-scale clinical trials, but it remains unclear whether their benefit stems from a superior pharmacologic profile to unfractionated heparin or is determined by an enhanced ability to suppress thrombin generation (by virtue of a direct anti-Xa effect). Regardless, investigators have become increasingly interested in factor Xa as a potential target for antithrombotic therapy. A number of naturally occurring Xa antagonists have been identified. Work with recombinant forms of these proteins confirms that factor Xa inhibition can suppress thrombin generation in a variety of animal thrombosis models. Accordingly, a number of synthetic direct and indirect Xa antagonists are under development for the prevention and treatment of thrombotic disorders. The following review summarizes the evolution of factor Xa antagonists.
Spencer
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FA
Cardiovascular Thrombosis Research Center, UMass Memorial Medical Center, 55 Lake Avenue North, Worcester, MA 01655, USA.
Becker
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D000818:Animals; D000990:Antithrombin III / Q000627:therapeutic use; D060829:Arthropod Proteins; D002318:Cardiovascular Diseases / Q000188:drug therapy*; D005170:Factor X / Q000037:antagonists & inhibitors*; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D015801:Helminth Proteins / Q000627:therapeutic use; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007447:Invertebrate Hormones / Q000627:therapeutic use; D007865:Leeches; D009281:Naphthalenes / Q000627:therapeutic use; D009844:Oligosaccharides / Q000627:therapeutic use; D010455:Peptides / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D011422:Propionates / Q000627:therapeutic use
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D060829:Arthropod Proteins; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D015801:Helminth Proteins; D006495:Heparin, Low-Molecular-Weight; D036341:Intercellular Signaling Peptides and Proteins; D007447:Invertebrate Hormones; D009281:Naphthalenes; D009844:Oligosaccharides; C064764:PENTA; D010455:Peptides; D010880:Piperidines; D011422:Propionates; C111032:YM 60828; C108605:anti-coagulant protein 5, Ancylostoma caninum; C063967:tick anticoagulant peptide; C053155:antistasin; D000990:Antithrombin III; D005170:Factor X