1. Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362 .
- Author
-
Lowe MA, Cardenas A, Valentin JP, Zhu Z, Abendroth J, Castro JL, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer DD, MacCoss M, Rowley JH, Rosseels ML, Royer L, Taylor RD, Wong M, Zaccheo O, Chavan VP, Ghule GA, Tapkir BK, Burrows JN, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jiménez-Díaz MB, Striepen J, Fairhurst KJ, Yeo T, Fidock DA, Cowman AF, Favuzza P, Crespo-Fernandez B, Gamo FJ, Goldberg DE, Soldati-Favre D, Laleu B, and de Haro T
- Subjects
- Animals, Humans, Plasmodium falciparum metabolism, Aspartic Acid Endopeptidases, Antimalarials pharmacology, Antimalarials therapeutic use, Malaria drug therapy, Folic Acid Antagonists
- Abstract
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 ( t
1/2 ) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t1/2 . UCB7362 is estimated to achieve 9 log 10 unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria.- Published
- 2022
- Full Text
- View/download PDF