Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362.

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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, Jimenez-Diaz 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, de Haro T

Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362.

J Med Chem. 2022 Oct 27;65(20):14121-14143. doi: 10.1021/acs.jmedchem.2c01336. Epub 2022 Oct 10.

PubMed ID

36216349 [ View in PubMed

]

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 (t1/2) 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 9log10 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.

DrugBank Data that Cites this Article

Drugs

UCB7362

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
UCB7362	Plasmepsin X	Protein	Plasmodium falciparum (isolate 3D7)	Yes	Inhibitor Binder	Details
UCB7362	Plasmepsin X	Protein	Plasmodium falciparum (isolate NF54)	Yes	Inhibitor Binder	Details