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

Martin A. Lowe, Alvaro Cardenas, Jean Pierre Valentin, Zhaoning Zhu, Jan Abendroth, Jose L. Castro, Reiner Class, Annie Delaunois, Renaud Fleurance, Helga Gerets, Vitalina Gryshkova, Lloyd King, Donald D. Lorimer, Malcolm Maccoss, Julian H. Rowley, Marie Luce Rosseels, Leandro Royer, Richard D. Taylor, Melanie Wong, Oliver ZaccheoVishal P. Chavan, Gokul A. Ghule, Bapusaheb K. Tapkir, Jeremy N. Burrows, Maëlle Duffey, Matthias Rottmann, Sergio Wittlin, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Josefine Striepen, Kate J. Fairhurst, Tomas Yeo, David A. Fidock, Alan F. Cowman, Paola Favuzza, Benigno Crespo-Fernandez, Francisco Javier Gamo, Daniel E. Goldberg, Dominique Soldati-Favre, Benoît Laleu, Teresa De Haro

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)14121-14143
Number of pages23
JournalJournal of Medicinal Chemistry
Volume65
Issue number20
DOIs
StatePublished - Oct 27 2022

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