Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.
Abstract-The dose-limiting issue with available anticoagulant therapies is bleeding. Is there an approach that could provide antithrombotic protection with reduced bleeding? One hypothesis is that targeting proteases upstream from the common pathway provides a reduction in thrombin sufficient to impede occlusive thrombosis yet allows enough thrombin generation to support hemostasis. The impairment of intrinsic coagulation by selective inhibition of factor XI (FXI) leaves the extrinsic and common pathways of coagulation intact, making FXI a drug target. This concept is supported by the observation that human deficiency in FXI results in a mild bleeding disorder compared with other coagulation factor deficiencies, and that elevated levels of FXI are a risk factor for thromboembolic disease. Moreover, FXI knockout mice have reduced thrombosis with little effect on hemostasis. The results from genetic models have been supported by studies using neutralizing antibodies, peptide inhibitors, and small-molecule inhibitors. These agents impede thrombosis without affecting bleeding time in a variety of experimental animals, including primates. Together, these data strongly support FXIa inhibition as a viable method to increase the ratio of benefit to risk in an antithrombotic drug. (Arterioscler Thromb Vasc Biol. 2010;30:388-392.)Key Words: intrinsic pathway Ⅲ coagulation Ⅲ factor XI Ⅲ thrombosis The Need for Improved Anticoagulant TherapyHemostasis is an adaptive process that maintains blood in a fluid state and preserves vasculature integrity. Thrombosis is a maladaptive process of vascular occlusion and remains a primary cause of cardiovascular morbidity and mortality. Antithrombotic therapy is effective for the prevention and treatment of thromboembolic disease. However, the established oral anticoagulant warfarin has numerous limitations, including lack of reversibility, a steep dose response, food and multiple drug-drug interactions, need for monitoring, and a narrow therapeutic index. The availability of newer oral anticoagulants, such as direct and selective inhibitors of factor Xa (FXa) and thrombin, has overcome many of these liabilities; however, dose-dependent bleeding continues to be observed. 1,2 An overlap of antithrombotic benefit and a disruption of hemostasis are not unexpected given that both processes involve interactions between the vessel wall, platelets, blood coagulation, and fibrinolysis. Improving the risk to benefit ratio remains a viable goal for antithrombotic drug See accompanying article on page 369discovery. This requires selecting a molecular target that defines a difference between hemostasis and thrombosis. Selecting such a target derives from the detailed study of human physiology and animal models. A good example is the inhibition of blood coagulation FXIa as a novel mechanism for preventing and treating thromboembolic diseases. Role of FXIa in Blood CoagulationBlood coagulation is the coordinated activation of plasma proteases, their cofactors, and platelets. The end product is the pr...
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