Design of Small-Molecule Active-Site Inhibitors of the S1A Family Proteases as Procoagulant and Anticoagulant Drugs

Abstract

Vitamin K antagonists (VKA) have long been the default drugs for anticoagulant management in venous thrombosis. While efficacious, they are difficult to use due to interpatient dose-response variability and the risks of bleeding. The approval of fondaparinux, a heparin-derived factor Xa (fXa) inhibitor, provided validation for the development of direct oral anticoagulants (DOAC), and currently such inhibitors of thrombin and fXa are in clinical use. These agents can be used without regular coagulation monitoring, but the inherent risk of bleeding complications associated with blocking the common coagulation pathway remains. Efforts are now underway to develop DOACs that inhibit components of the intrinsic and extrinsic coagulation cascades upstream of thrombin and fX. Evidence from humans and from transgenic animal models suggests that this strategy may provide a better therapeutic margin between antithrombotic and antihemostatic effects. Here the design of active-site inhibitors of S1A proteases involved in coagulation and fibrinolysis is summarized.

A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

“…The inhibitor binding site of these two sets of proteins are usually very large. For the ease of analysis and understanding of the binding event, this long site was divided into four subsites or pockets, S1, S2, S3 and S4 [ 1 , 23 , 24 , 26 ]. Due to this binding pose, the fragment of the inhibitor that occupies the S1 pocket is surrounded by the protein from all sides and the fragments of the inhibitor that occupies the S3 and S4 pockets are crawling over the surface and one side of the ligand is exposed to solvent.…”

“…All these conditions are, in general, categorized as thromboembolic disorders which continues to be one of the major causes of mortality and disability in the modern world. Anticoagulants are the established treatments to manage thromboembolic disorders [ 1 , 2 , 3 ].…”

“…Heparin and warfarin are the earliest therapies as anticoagulants for thromboembolic disorders, but these agents regulate the coagulation process through the indirect pathway and have restricted use due to their bleeding risk [ 4 ]. In recent years, several FXa (Factor Xa) inhibitors have been approved as the direct oral anticoagulants (DOAC) by the FDA for the treatment of these thromboembolic disorders, but they are not completely devoid of bleeding risk since this target falls under the common pathway [ 1 , 5 ] of coagulation process. Some of the FXa inhibitors are apixaban [ 6 ], rivaroxaban [ 7 ], letaxaban [ 8 ] and eribaxaban [ 9 ].…”

“…Selective inhibition of FIXa that falls under the intrinsic pathway, which is right above FXa in the downstream coagulation propagation ( Figure S1 , shown in the Supplementary Materials ), is hypothesized and validated for improved bleeding related risk with similar efficacy compared to the FXa inhibitors. The basic tenet of this strategy is the selective regulation of the intrinsic pathway through selective therapeutic agents that would not be affecting the targets in the extrinsic pathway and the common pathway [ 1 , 2 , 3 , 10 , 11 , 12 , 13 , 14 ].…”

Recent advances in the discovery and development of factor XI/XIa inhibitors

“…Finding appropriate routes of administration and delivery systems as well as developing molecules with optimal pharmacokinetic profiles appear to be the focus of most of the programs targeting FXI/FXIa. Importantly, the nonselectivity of the active site peptidomimetic inhibitors, particularly toward plasma kallikrein, trypsin, and/or chymotrypsin appears to be an issue, although diverse drug design strategies have been considered (Figure ). Furthermore, an effective antidote to treat cases of excessive anticoagulation may be needed and perhaps should be considered.…”