6QMT

Complement factor D in complex with the inhibitor 2-(2-(3'-(aminomethyl)-[1,1'-biphenyl]-3-carboxamido)phenyl)acetic acid

Summary for 6QMT

• Entry DOI: 10.2210/pdb6qmt/pdb
• Related: 6QMR
• Descriptor: Complement factor D, 2-[2-[[3-[3-(aminomethyl)phenyl]phenyl]carbonylamino]phenyl]ethanoic acid (3 entities in total)
• Functional Keywords: complement factor d, inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 54916.68

Authors

Karki, R.,Powers, J.,Mainolfi, N.,Anderson, K.,Belanger, D.,Liu, D.,Jendza, K.,Gelin, C.F.,Solovay, C.,Mac Sweeeny, A.,Delgado, O.,Crowley, M.,Liao, S.-M.,Argikar, U.A.,Flohr, S.,La Bonte, L.R.,Lorthiois, E.L.,Vulpetti, A.,Cumin, F.,Brown, A.,Adams, C.,Jaffee, B.,Mogi, M. (deposition date: 2019-02-08, release date: 2019-04-24, Last modification date: 2024-11-06)

Primary citation

Karki, R.G.,Powers, J.,Mainolfi, N.,Anderson, K.,Belanger, D.B.,Liu, D.,Ji, N.,Jendza, K.,Gelin, C.F.,Mac Sweeney, A.,Solovay, C.,Delgado, O.,Crowley, M.,Liao, S.M.,Argikar, U.A.,Flohr, S.,La Bonte, L.R.,Lorthiois, E.L.,Vulpetti, A.,Brown, A.,Long, D.,Prentiss, M.,Gradoux, N.,de Erkenez, A.,Cumin, F.,Adams, C.,Jaffee, B.,Mogi, M.
Design, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement Pathway.
J.Med.Chem., 62:4656-4668, 2019

PubMed Abstract: 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.

PubMed: 30995036
DOI: 10.1021/acs.jmedchem.9b00271

Experimental method

X-RAY DIFFRACTION (1.8 Å)