Design of Novel Series of Antimalarial PMX Inhibitors with Increased Half-Life via Molecular Property Optimization.

Autor: Sakata K; UCB, 216 Bath Road, Slough SL1 3WE, United Kingdom., Lowe MA; UCB, 216 Bath Road, Slough SL1 3WE, United Kingdom., Xuan M; UCB, 216 Bath Road, Slough SL1 3WE, United Kingdom., Bruffaerts J; UCB, 216 Bath Road, Slough SL1 3WE, United Kingdom., Stasi LP; UCB, 216 Bath Road, Slough SL1 3WE, United Kingdom., Lallemand B; UCB, Chem. du Foriest 1, 1420 Braine-l'Alleud, Belgium., Cardenas A; UCB, Chem. du Foriest 1, 1420 Braine-l'Alleud, Belgium., Taylor RD; UCB, 216 Bath Road, Slough SL1 3WE, United Kingdom., Vidler LR; UCB, 216 Bath Road, Slough SL1 3WE, United Kingdom., King L; UCB, 216 Bath Road, Slough SL1 3WE, United Kingdom., Valentin JP; UCB, Chem. du Foriest 1, 1420 Braine-l'Alleud, Belgium., Laleu B; Medicines for Malaria Venture, ICC, Route de Pré-Bois 20, 1215 Geneva, Switzerland., de Haro T; UCB, Chem. du Foriest 1, 1420 Braine-l'Alleud, Belgium.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2023 Oct 20; Vol. 14 (11), pp. 1582-1588. Date of Electronic Publication: 2023 Oct 20 (Print Publication: 2023).
DOI: 10.1021/acsmedchemlett.3c00404
Abstrakt: Plasmepsin X (PMX) has been identified as a multistage antimalarial target. PMX is a malarial aspartyl protease essential for merozoite egress from infected red blood cells and invasion of the host erythrocytes. Previously, we reported the identification of PMX inhibitors by structure-based optimization of a cyclic guanidine core. Preclinical assessment of UCB7362 , which displayed both in vitro and in vivo antimalarial activity, revealed a suboptimal dose paradigm (once daily dosing of 50 mg for 7 days for treatment of uncomplicated malaria) relative to current standard of care (three-dose regime). We report here the efforts toward extending the half-life ( t 1/2 ) by reducing metabolic clearance and increasing volume of distribution ( V ss). Our efforts culminated in the identification of a biaryl series, with an expected longer t 1/2 in human than UCB7362 while maintaining a similar in vitro off-target hit rate.
Competing Interests: The authors declare no competing financial interest.
(© 2023 American Chemical Society.)
Databáze: MEDLINE
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