Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders

Abstract

Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.

Design and synthesis of novel factor XIa Inhibitors with bicyclic isoquinoline and naphthalene fragments

“…Currently, the isosteric replacement of aniline remain limited [40]. Our group (data not reported) and Bayer have recently demonstrated that substituting aniline with saturated ring amines leads to a loss of inhibitory activity against FXIa [17]. Inspired by the successful annulation strategy employed in the discovery of the top-selling FXa inhibitor apixaban [41], a similar approach was considered to replace the amide motif of asundexian.…”

“…Water was added, extracted with CH 2 Cl 2 , washed with brine, dried over Na 2 SO 4 , concentrated to give compound 16 as a yellow (2.2 g, yield 88.8%). 1 1-(7-Bromoisoquinolin-3-yl)propan-1-ol (17) Compound 16 (2.2 g, 9.3 mmol) was added to 20 mL of tetrahydrofuran under nitrogen atmosphere. Ethylmagnesium bromide (2.5 g, 18.6 mmol) was added dropwise at -80°C.…”

“…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].…”

Drug–Drug Interactions of FXI Inhibitors: Clinical Relevance

“…More recently, an in vitro analysis determined that asundexian is a P-gp substrate, and it is predominantly metabolized via carboxylesterase 1 and, to a lesser extent, via CYP3A4 [ 45 ]. Asundexian did not affect CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2E1, CYP2J2, and CYP3A4 activity, while a weak inhibitory potential on CYP2C8, CYP2C9, CYP1A1, and CYP2D6 was observed [ 46 ]. Thus, both milvexian and asundexian are both P-gp substrates as the currently approved DOACs (dabigatran, edoxaban, apixaban, and rivaroxaban) ( Table 2 ), and therefore, strong inhibitors of this drug transporter can increase absorption and exposure of these anticoagulants and the risk of bleeding [ 2 ].…”

“…Pharmacokinetic and pharmacodynamic characteristics of oral anti thrombin, FXa, and FXIa.Table has been modified from Ferri, N. et al, 2022 [2] with data on milvexian and asundexian derived from Perera, V. et al, 2022 [42] and from Roehrig, S. et al, 2023, Piel, I. et al, 2023, and Kanefendt, F. et al, 2023[44,46,47].…”