TY - JOUR
T1 - Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362
AU - Lowe, Martin A.
AU - Cardenas, Alvaro
AU - Valentin, Jean Pierre
AU - Zhu, Zhaoning
AU - Abendroth, Jan
AU - Castro, Jose L.
AU - Class, Reiner
AU - Delaunois, Annie
AU - Fleurance, Renaud
AU - Gerets, Helga
AU - Gryshkova, Vitalina
AU - King, Lloyd
AU - Lorimer, Donald D.
AU - Maccoss, Malcolm
AU - Rowley, Julian H.
AU - Rosseels, Marie Luce
AU - Royer, Leandro
AU - Taylor, Richard D.
AU - Wong, Melanie
AU - Zaccheo, Oliver
AU - Chavan, Vishal P.
AU - Ghule, Gokul A.
AU - Tapkir, Bapusaheb K.
AU - Burrows, Jeremy N.
AU - Duffey, Maëlle
AU - Rottmann, Matthias
AU - Wittlin, Sergio
AU - Angulo-Barturen, Iñigo
AU - Jiménez-Díaz, María Belén
AU - Striepen, Josefine
AU - Fairhurst, Kate J.
AU - Yeo, Tomas
AU - Fidock, David A.
AU - Cowman, Alan F.
AU - Favuzza, Paola
AU - Crespo-Fernandez, Benigno
AU - Gamo, Francisco Javier
AU - Goldberg, Daniel E.
AU - Soldati-Favre, Dominique
AU - Laleu, Benoît
AU - De Haro, Teresa
N1 - Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/10/27
Y1 - 2022/10/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85139827473&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.2c01336
DO - 10.1021/acs.jmedchem.2c01336
M3 - Article
C2 - 36216349
AN - SCOPUS:85139827473
SN - 0022-2623
VL - 65
SP - 14121
EP - 14143
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 20
ER -