Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives

Abstract

Factor XIa (FXIa) in the intrinsic pathway of the coagulation process has been proven to be an effective and safe target for anticoagulant discovery with limited or no bleeding. Numerous small-molecule FXIa inhibitors (SMFIs) with various scaffolds have been identified in the early stages of drug discovery. They have served as the foundation for the recent discovery of additional promising SMFIs with improved potency, selectivity, and pharmacokinetic profiles, some of which have entered clinical trials for the treatment of thrombosis. After reviewing the coagulation process and structure of FXIa, this perspective discusses the rational or structure-based design, discovery, structure−activity relationships, and development of SMFIs disclosed in recent years. Strategies for identifying more selective and druggable SMFIs are provided, paving the way for the design and discovery of more useful SMFIs for anticoagulation therapy.

Determination of the Potential Clinical Benefits of Small Molecule Factor XIa Inhibitors in Arterial Thrombosis

“…ONO-7684 (or ONO-5450598) is an imidazole-based selective FXIa inhibitor, which competitively and reversibly binds to FXIa. − Intravenous infusion of ONO-7684 prolonged aPTT and decreased thrombus weight in monkeys with the arteriovenous shunt model of thrombosis. In addition, oral administration of ONO-7684 did not alter bleeding time following a nail-cut bleeding model in monkeys, whereas rivaroxaban significantly increased the bleeding time. − The oral bioavailability of ONO-7684 varied between species, i.e., 59% in rats, 81% in monkeys, and 88% in dogs. − …”

“…In addition, oral administration of ONO-7684 did not alter bleeding time following a nail-cut bleeding model in monkeys, whereas rivaroxaban significantly increased the bleeding time. 82 − 84 The oral bioavailability of ONO-7684 varied between species, i.e., 59% in rats, 81% in monkeys, and 88% in dogs. 82 − 84…”

“… 82 − 84 The oral bioavailability of ONO-7684 varied between species, i.e., 59% in rats, 81% in monkeys, and 88% in dogs. 82 − 84…”

Design and Synthesis of Novel Factor XIa Inhibitors with Bicyclic Isoquinoline and Naphthalene Fragments

“…thrombotic e cacy without an impact on normal hemostasis in these animal models [8]. Most importantly, several approaches to inhibit FXI synthesis or FXIa activity are in clinical phases [15], with small molecule FXIa inhibitors such as asundexian and milvexian advancing to Phase III clinical trial [16,17]. Both compounds have demonstrated lower or comparable bleeding rates compared to placebo or standard anticoagulant care in Phase II clinical trials [18,19].In addition to inhibiting FXIa, some FXIa inhibitors also demonstrate substantial inhibition of plasma PKa, a coagulation factors in the contact pathway (Figure 1) [20].…”