Perspectives on Factor Xa Inhibition

Abstract

Blood coagulation involves a complex cascade of enzymatic reactions, ultimately generating fibrin, the basis of all blood clots. This cascade is comprised of two arms, the intrinsic and extrinsic pathways which converge at factor Xa to form the common pathway. Factor Xa activates prothrombin to thrombin, which in turn catalyzes the conversion of fibrinogen to fibrin. Recently, both natural and synthetic factor Xa inhibitors have shown promising pharmacological effects in animal models of thrombosis. Accordingly, factor Xa has emerged as a compelling target for pharmacological intervention and much recent effort has focused on selective and potent inhibition of this key enzyme. Factor Xa and other enzymes in the coagulation cascade belong to the trypsin-like serine protease family, the various members of which are involved in numerous physiological functions in the body. Hence, to avoid toxicity and adverse side effects, it is important to selectively inhibit the target enzyme. Achieving the needed selectivity has proved challenging due to the high degree of structural homology around the active site of this class of enzymes. This article provides a brief review of the strategies currently being employed to develop oral anticoagulants and, more specifically, the structural features of protein-ligand binding that have been utilized to achieve potency and selectivity toward factor Xa. Additionally, selected lead molecules will be discussed to highlight binding motifs used to attain both potency and selectivity in drug candidates.

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

“…Other serine proteases, such as aPC and tPA, have important anticoagulant and fibrinolytic functions. Detailed structural differences and similarities of these serine proteases have been discussed, [48][49][50][51][52] and only the important differences will be highlighted here. In the 1990s, the structure of fXa was determined by X-ray crystallography (Protein Data Bank (PDB) code 1HCG), 53 and the first crystal structures of complexes between fXa and small molecule inhibitors were reported soon thereafter (PDB codes 1FAX, 1XKA, and 1XKB).…”

Pharmacokinetics, Biotransformation, and Mass Balance of Edoxaban, a Selective, Direct Factor Xa Inhibitor, in Humans

“…Factor Xa (FXa) is a target for new anticoagulants and is located at the junction of the intrinsic and extrinsic pathways of coagulation. Free FXa is responsible for the generation of the first trace amounts of thrombin, and FXa within the prothrombinase complex (bound to the surface of activated platelets) induces the propagation phase of thrombin generation from prothrombin (Rai et al, 2001;Weitz, 2011).…”

Global Anticoagulant Effects of a Synthetic Anti-Factor Xa Inhibitor (DX-9065a): Implications for Interventional Use

“…Synthetic direct factor Xa inhibitor DX-9065a, 10,5, and 0,ug/mL (saline control). Thrombelastography was performed, and five different TEG parameters were calculated accordingly.…”

“…While clinical development of several naturally occurring direct anti-factor Xa agents such as antistatin, tick anticoagulant peptide (TAP), and yagin is delayed, there is rapid development of newer synthetic inhibitors of factor Xa such as JTV-803, DX-9065a, and Bay 59-7939. DX-9065a is a synthetic peptidomimetic direct factor Xa inhibitor, and is in different phases of clinical trials at this time (5)(6)(7). The factor Xa inhibitors exhibit a higher margin of safety when compared to the antithrombin agents (8)(9)(10).…”