Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of
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:
27 10 2022
27 10 2022
Historique:
pubmed:
11
10
2022
medline:
29
10
2022
entrez:
10
10
2022
Statut:
ppublish
Résumé
Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life (
Identifiants
pubmed: 36216349
doi: 10.1021/acs.jmedchem.2c01336
pmc: PMC9620073
doi:
Substances chimiques
Antimalarials
0
plasmepsin
EC 3.4.23.38
Aspartic Acid Endopeptidases
EC 3.4.23.-
Folic Acid Antagonists
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14121-14143Références
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