Discovery and characterization of potent, efficacious, orally available antimalarial plasmepsin X inhibitors and preclinical safety assessment of UCB7362

Lowe, M. A. and Cardenas, A. and Valentin, J. P. and Zhu, Z. and Abendroth, J. and Castro, J. L. and Class, R. and Delaunois, A. and Fleurance, R. and Gerets, H. and Gryshkova, V. and King, L. and Lorimer, D. D. and MacCoss, M. and Rowley, J. H. and Rosseels, M. L. and Royer, L. and Taylor, R. D. and Wong, M. and Zaccheo, O. and Chavan, V. P. and Ghule, G. A. and Tapkir, B. K. and Burrows, J. N. and Duffey, M. and Rottmann, M. and Wittlin, S. and Angulo-Barturen, I. and Jiménez-Díaz, M. B. and Striepen, J. and Fairhurst, K. J. and Yeo, T. and Fidock, D. A. and Cowman, A. F. and Favuzza, P. and Crespo-Fernandez, B. and Gamo, F. J. and Goldberg, D. E. and Soldati-Favre, D. and Laleu, B. and de Haro, T.. (2022) Discovery and characterization of potent, efficacious, orally available antimalarial plasmepsin X inhibitors and preclinical safety assessment of UCB7362. Journal of medicinal chemistry, 65 (20). pp. 14121-14143.

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Official URL: https://edoc.unibas.ch/90627/

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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.

Faculties and Departments:	09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:	Rottmann, Matthias and Wittlin, Sergio
Item Type:	Article, refereed
Article Subtype:	Research Article
ISSN:	0022-2623
Note:	Publication type according to Uni Basel Research Database: Journal article
Identification Number:	doi: 10.1021/acs.jmedchem.2c01336 pmid: 36216349
Last Modified:	27 Dec 2022 12:18
Deposited On:	27 Dec 2022 12:18

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