5NAR

Complement factor D in complex with the inhibitor (S)-pyrrolidine-1,2-dicarboxylic acid 1-[(1-carbamoyl-1H-indol-3-yl)-amide] 2-[(3-trifluoromethoxy-phenyl)-amide]

Summary for 5NAR

• Entry DOI: 10.2210/pdb5nar/pdb
• Descriptor: Complement factor D, SULFATE ION, (2~{S})-~{N}1-(1-aminocarbonylindol-3-yl)-~{N}2-[3-(trifluoromethyloxy)phenyl]pyrrolidine-1,2-dicarboxamide, ... (4 entities in total)
• Functional Keywords: hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P00746
• Total number of polymer chains: 1
• Total formula weight: 25310.60

Authors

Mac Sweeney, A.,Ostermann, N. (deposition date: 2017-02-28, release date: 2017-06-28, Last modification date: 2024-11-13)

Primary citation

Lorthiois, E.,Anderson, K.,Vulpetti, A.,Rogel, O.,Cumin, F.,Ostermann, N.,Steinbacher, S.,Mac Sweeney, A.,Delgado, O.,Liao, S.M.,Randl, S.,Rudisser, S.,Dussauge, S.,Fettis, K.,Kieffer, L.,de Erkenez, A.,Yang, L.,Hartwieg, C.,Argikar, U.A.,La Bonte, L.R.,Newton, R.,Kansara, V.,Flohr, S.,Hommel, U.,Jaffee, B.,Maibaum, J.
Discovery of Highly Potent and Selective Small-Molecule Reversible Factor D Inhibitors Demonstrating Alternative Complement Pathway Inhibition in Vivo.
J. Med. Chem., 60:5717-5735, 2017

PubMed Abstract: 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.

PubMed: 28621538
DOI: 10.1021/acs.jmedchem.7b00425

Experimental method

X-RAY DIFFRACTION (1.55 Å)