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

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.

• Authors: 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 Zaccheo, Vishal 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 20 Pg. 14121-14143 (10 27 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 36216349 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimalarials
• plasmepsin
• Aspartic Acid Endopeptidases
• Folic Acid Antagonists

Topics

• Animals
• Humans
• Antimalarials (pharmacology, therapeutic use)
• Plasmodium falciparum (metabolism)
• Aspartic Acid Endopeptidases
• Malaria (drug therapy)
• Folic Acid Antagonists