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

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.