Discovery of (3R,4R)‑15: An Advanced Factor B Inhibitor Entering Phase 3 for Complement-Mediated Diseases

The alternative pathway (AP) of the complement system
plays a critical
role in the pathogenesis of various human diseases, including age-related
macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH),
atypical hemolytic uremic syndrome (aHUS), and several glomerular
diseases. Although the approved drug Iptacopan is available,
it requires twice-daily oral dosing, resulting in suboptimal patient
compliance. Using a scaffold-hopping strategy, we identified the clinical
candidate (3R,4R)-15, which exhibits
potent inhibitory activity against factor B (FB) and the AP, with
IC50 values of 10.2 nM and 59.3 nM, respectively. Furthermore,
this compound exhibits significantly improved pharmacokinetic properties,
including an oral bioavailability of 69.2% in mice. Preliminary clinical
studies indicate that (3R,4R)-15 has
promising efficacy in patients with PNH. Its once-daily dosing regimen
also offers the potential to markedly improve patient compliance. (3R,4R)-15 is currently in Phase 3 trials
evaluating its efficacy for the treatment of PNH.