DX‐9065a, a Direct Inhibitor of Factor Xa

Abstract

The synthetic compound DX-9065a represents a low molecular weight, direct, competitive inhibitor of factor Xa (FXa) with a high affinity and selectivity for the enzyme. Under experimental conditions DX-9065a exerts strong anticoagulant actions in vitro and in vivo and is antithrombotically effective in various thrombosis models. It inhibits proliferation of vascular smooth muscle cells in cell culture systems as well as in in vivo models. As a small molecule inhibitor, DX-9065a inactivates both free and fibrin-bound FXa. By this mechanism it effectively affects the clot-associated procoagulant activity which might be responsible for the propagation of intravascular thrombi as well as for recurrent thrombosis and thrombotic reocclusion after lysis. Although DX-9065a is effective after oral administration, its oral bioavailability is relatively low and seems not to be sufficient for a long-term therapeutic use of the drug. However, first clinical trials in healthy volunteers and in patients with cardiovascular diseases demonstrated a predictable pharmacokinetic and pharmacodynamic behavior of DX-9065a after either intravenous bolus injection or constant infusion, as well as its high safety, especially a lower bleeding risk compared with other commonly used drugs. Further experimental studies and ongoing clinical trials will evaluate the inhibitory profile of the drug, its effectiveness and its possible superiority over other drug regimens in various cardiovascular indications.

Evaluation of Plaque Stability of Advanced Atherosclerotic Lesions in Apo E-Deficient Mice after Treatment with the Oral Factor Xa Inhibitor Rivaroxaban

“…Several studies demonstrated that inhibition of Factor Xa reduces VSMC proliferation [31], and restenosis after balloon angioplasty [31–35]. At the molecular level, wound healing and fibrosis share similar mechanisms, including fibroblast migration, proliferation and subsequent differentiation into myofibroblasts that typically express α -SM actin [36].…”

Blood coagulation factor Xa as an emerging drug target

“…In the context of vascular remodeling during atherosclerosis, restenosis and intimal hyperplasia, FXa promotes smooth muscle cell proliferation and migration [31,[73][74][75][76] and (as indicated above) FXa induces the differentiation of fibroblasts into myofibroblasts [61]. These data support the hypothesis that FXa-dependent signal transduction plays an important role in tissue remodeling.…”

“…These data support the hypothesis that FXa-dependent signal transduction plays an important role in tissue remodeling. In line with this hypothesis, FXa inhibition reduces vascular smooth muscle cell proliferation [74] and restenosis after balloon angioplasty [74,[77][78][79][80]. However, the inhibition of FXa also diminishes thrombin generation, which is well-known to be deleterious in vascular remodeling [81].…”

Current concepts for the prevention of venous thromboembolism

“…DX-9065a is a reversible, highly selective competitor for factor Xa. It has been shown to be an effective anticoagulant whether applied subcutaneously, intravenously or orally [40], although the oral bioavailability of DX-9065a is too low for clinical usability [41]. First clinical trials in patients with coronary artery disease were positive and phase II trials initiated.…”