Development of Orally Active Thrombin Inhibitors for the Treatment of Thrombotic Disorder Diseases

Abstract

Thrombotic disorders represent the major share of the various cardiovascular diseases, and significant progress has been made in the development of synthetic thrombin inhibitors as new anticoagulants. In addition to the development of highly potent and selective inhibitors with improved safety and suitable half-life, several allosteric inhibitors have been designed and synthesized, that did not fully nullify the procoagulant signal and thus could result in reduced bleeding complications. Furthermore, natural products with thrombin inhibitory activity have been isolated, and some natural products have been modified in order to improve their inhibitory activity and metabolic stability. This review summarizes the development of orally active thrombin inhibitors for the treatment of thrombotic disorder diseases, which could serve as a reference for the interested researchers.

Purification and Characterization of a Fibrinolytic Enzyme from Marine Bacillus velezensis Z01 and Assessment of Its Therapeutic Efficacy In Vivo

“…The accumulation of insoluble fibrin in a blood vessel usually leads to thrombosis, which further result in thrombotic diseases (TDs), such as myocardial infarction, stroke, and venous thromboembolism [ 1 ]. TDs account for approximately 31% of all worldwide deaths and are rapidly increasing in developing countries [ 2 ].…”

Theoretical Study of Molecular Structure and Physicochemical Properties of Novel Factor Xa Inhibitors and Dual Factor Xa and Factor IIa Inhibitors

“…Synthetic inhibitors such as betrixaban, razaxaban, eribaxaban, fidexaban, darexaban (YM150), letaxaban (TAK-442) are members of a new class of orally available fXa inhibitors. In addition to the abovementioned direct fXa inhibitors, dual thrombin/fXa inhibitors such as tanogitran, RWJ-445167, and SAR107375 have also been developed [7,8,9]. Despite a number of experimental structural information about binding models of novel anticoagulants targeting thrombin, fXa or both, experimental studies concerned with the systematic comparative studies of their physicochemical and pharmacokinetic parameters are scarce, and most of novel drug were discovered serendipitously [10].…”

Modulating hydrogen-bond basicity within the context of protein-ligand binding: A case study with thrombin inhibitors that reveals a dominating role for desolvation

“…These diseases, collectively, are a leading cause of mortality and morbidity, particularly among elderly patients [8]. Thrombin inhibition, therefore, provides a validated approach for anticoagulation therapy; and over the past decades, there have been significant efforts to discover small molecules that act as direct thrombin inhibitors [9][10][11]. These efforts have resulted in the introduction of dabigatran, a direct thrombin inhibitor, into the market as a prophylaxis to reduce the risk of thromboembolism [12].…”