Recent Advances in the Discovery and Development of Direct Coagulation Factor Xa Inhibitors

Abstract

Coronary heart disease (CHD) is the leading cause of mortality and morbidity in the United States. Currently, there are approximately 12 million Americans with CHD, which is most frequently caused by atherosclerosis. The thrombotic complications of atherosclerosis, such as acute coronary syndrome and ischemic stroke, can be fatal and those who survive such events have a far greater risk of future cardiovascular events. This huge medical need cries out for improved novel anticoagulants, antiplatelet agents, and profibrinolytic agents. These agents will successfully respond to the medical need by providing safe, effective, and easily administered treatments that have little, if any, drug and food interactions and that require minimal monitoring. The currently approved antiplatelet agent, clopidogrel, has satisfied some of these requirements and has played a large role in expanding the antithrombotic market over the past few years. New antithrombotics approaching the marketplace, such as the prodrug thrombin inhibitor ximelagatran, have promise in expanding the antithrombotic market further. Over the past two decades, the pharmaceutical industry has mounted a huge effort to develop antithrombotics that function by inhibiting key enzymes positioned at "higher" levels of the coagulation system. Direct inhibitors of factor Xa, which may provide a better safety and efficacy profile than currently available agents, appear to be the next major class of antithrombotic agents poised to take the pharmaceutical industry one step closer to delivering the ideal antithrombotic agent. This review focuses on recent innovations in the discovery and development of potent parenteral and oral direct factor Xa inhibitors.

Extracellular Proteases as Targets for Drug Development

“…Another promissing target is factor Xa 110 . Factor Xa inhibitors could effectively prevent the generation of thrombin without affecting existing thrombin levels.…”

A new release on life: emerging concepts in proteolysis and parasite invasion

“…HIV) provide encouragement for the concept of similarly developing drugs to target apicomplexan proteases. Serine proteases may present particular challenges as drug targets but they are not beyond the capabilities of drug developers, as demonstrated by ongoing clinical trials of inhibitors of the hepatitis C NS3-4A protease and thrombotic enzymes such as thrombin and Factor Xa (De Francesco et al, 2003;Gould and Leadley, 2003;Gustafsson, 2003). No selective rhomboid inhibitors are known, and given their apparent lack of sequence specificity, intramembrane location and numerous orthologues across evolution, the development of rhomboid inhibitors as drugs may be difficult.…”

An adaptive‐design dose‐ranging study of PD 0348292, an oral factor Xa inhibitor, for thromboprophylaxis after total knee replacement surgery

“…Short‐term thromboprophylaxis with low‐molecular‐weight heparins, fondaparinux or vitamin K antagonists (VKAs) after TKR are effective, but each has significant inconvenient and costly drawbacks . Factor Xa (FXa) is an attractive target for novel anticoagulants because of its specific role in the conversion of prothrombin to thrombin in the coagulation cascade, with little activity outside of coagulation . Several direct FXa inhibitors approved or in clinical development have emerged as oral anticoagulants poised to address many shortcomings of prior therapy .…”