Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo

5 years ago

Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo

Sha-Mei Liao, Andrea de Erkenez, Viral Kansara, Simon Rüdisser, Laura R. La Bonte, Stefanie Flohr, Aengus Mac Sweeney, Omar Delgado, Stefan Steinbacher, Bruce Jaffee, Edwige Lorthiois, Ronald Newton, Olivier Rogel, Anna Vulpetti, Jürgen Maibaum, Constanze Hartwieg, Solene Dussauge, Ulrich Hommel, Nils Ostermann, Louis Yang, Stefan Randl, Kamal Fettis, Upendra A. Argikar, Karen Anderson, Frederic Cumin, Laurence Kieffer

The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00425

DOI: 10.1021/acs.jmedchem.7b00425