Discovery of 4-((2
Atypical Hemolytic Uremic Syndrome
/ metabolism
Benzoic Acid
/ chemistry
Binding Sites
Catalytic Domain
Complement Factor B
/ antagonists & inhibitors
Crystallography, X-Ray
Drug Evaluation, Preclinical
Half-Life
Humans
Indoles
/ chemistry
Inhibitory Concentration 50
Macular Degeneration
/ metabolism
Molecular Dynamics Simulation
Structure-Activity Relationship
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
11 06 2020
11 06 2020
Historique:
pubmed:
20
2
2020
medline:
13
11
2020
entrez:
20
2
2020
Statut:
ppublish
Résumé
The alternative pathway (AP) of the complement system is a key contributor to the pathogenesis of several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. The serine protease factor B (FB) is a key node in the AP and is integral to the formation of C3 and C5 convertase. Despite the prominent role of FB in the AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we describe in more detail our efforts to identify FB inhibitors by high-throughput screening (HTS) and leveraging insights from several X-ray cocrystal structures during optimization efforts. This work culminated in the discovery of LNP023 (
Identifiants
pubmed: 32073845
doi: 10.1021/acs.jmedchem.9b01870
doi:
Substances chimiques
Indoles
0
Benzoic Acid
8SKN0B0MIM
Complement Factor B
EC 3.4.21.47
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM