Heterogeneity of Synthetic Factor Xa Inhibitors

Abstract

Heparins and vitamin K antagonists are the landmarks of antithrombotic treatment. Both of them were discovered by serendipity; they are multi-targeted drugs and share several limitations. New molecules have been designed in order to be both more selective concerning their biological target and more homogeneous in their biochemical structure aiming at an improved benefit/risk ratio in the treatment of thrombotic disease. In this article, we will review the pharmacological characteristics of the new synthetic direct or antithrombin dependent inhibitors of FXa in the light of the modern concept of blood coagulation process. We will also present the most recent data from the clinical trials with synthetic inhibitors of FXa. Among them, the synthetic pentasaccharide fondaparinux is the first synthetic and specific FXa inhibitor, which has been approved by health authorities in Europe and in the USA for the prophylaxis of venous thromboembolism in major orthopaedic surgery and is being approved for the treatment of pulmonary embolism and DVT as a single daily subcutaneous injection. The phase II dose-finding trial of the "meta-pentasaccharide" idraparinux administered subcutaneously once weekly in the secondary prevention of VTE has been completed. DX-9065a is the first direct synthetic inhibitor which has been studied in patients with coronary disease. Razaxaban, BAY59-7939, ZK-807834 and JTV-803 are orally active direct FXa inhibitors, which have been studied in phase II trials. Several other synthetic direct inhibitors of FXa (such as FXV673, YM60828, KFA-1411) are in a pre-clinical stage of research. From a clinical point of view, the results of recent trials with the synthetic specific FXa inhibitors clearly show that the inhibition of FXa is a critical point in the antithrombotic strategy.

A Novel Allosteric Pathway of Thrombin Inhibition

“…The nanomolar IC 50 values of direct inhibition suggest that sulfated DHPs are highly potent. This unexpected observation implies that sulfated DHPs are perhaps the first molecules outside of the peptides or peptidomimetics that show direct inhibition of thrombin and factor Xa (12)(13)(14)(15).…”

“…Structurally, most direct inhibitors of thrombin (DTIs) and factor Xa contain a guanidine or an amidine group that mimics the critical arginine residue at the P-1 3 site of the proteinase recognition sequence (14,15). DTIs and direct factor Xa inhibitors form major classes of clotting regulators that are considered to be superior to heparins primarily because of the expectation that they are likely to inhibit both circulating and clot-bound enzymes.…”

“…Although heparins require antithrombin to mediate their effect, DTIs and direct factor Xa inhibitors either bind in the active site or to an exosite on the enzyme to inhibit its proteolytic function (14,15). With a goal of developing inhibitors of factor Xa and thrombin that are less polyanionic and more hydrophobic than the heparins, we designed sulfated dehydropolymers (DHPs) (Fig.…”

Newer anticoagulants in 2009

“…2) [10]. Moreover, new antithrombotics although having the same target, i.e., specific FXa or specific FIIa inhibitors they do not have similar effect on PT or aPTT, and these observations provide further evidence for the heterogeneity of these drugs [11].…”

Recent Research Developments in the Direct Inhibition of Coagulation Proteinases – Inhibitors of the Initiation Phase

“…Interest in developing new heparins continues unabated [28,50]. A new pentasaccharide called idraparinux is being developed as once-a-week injection, but because of its structural similarity to fondaparinux it is likely to carry a similar bleeding risk and antidote problem [51][52][53][54].…”