Design, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement Pathway

Complement
factor D (FD), a highly specific S1 serine protease,
plays a central role in the amplification of the alternative complement
pathway (AP) of the innate immune system. Dysregulation of AP activity
predisposes individuals to diverse disorders such as age-related macular
degeneration, atypical hemolytic uremic syndrome, membranoproliferative
glomerulonephritis type II, and paroxysmal nocturnal hemoglobinuria.
Previously, we have reported the screening efforts and identification
of reversible benzylamine-based FD inhibitors (1 and 2) binding to the open active conformation of FD. In continuation
of our drug discovery program, we designed compounds applying structure-based
approaches to improve interactions with FD and gain selectivity against
S1 serine proteases. We report herein the design, synthesis, and medicinal
chemistry optimization of the benzylamine series culminating in the
discovery of 12, an orally bioavailable and selective
FD inhibitor. 12 demonstrated systemic suppression of
AP activation in a lipopolysaccharide-induced AP activation model
as well as local ocular suppression in intravitreal injection-induced
AP activation model in mice expressing human FD.