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    Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound 7 that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an in silico model to predict the brain-to-plasma partition coefficient Kp as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios (Kp,uu) to cure a CNS disease such as HAT.


    Dennis C Koester, Vanessa M Marx, Sarah Williams, Jan Jiricek, Maxime Dauphinais, Olivier René, Sarah L Miller, Lei Zhang, Debjani Patra, Yen-Liang Chen, Harry Cheung, Jonathan Gable, Suresh B Lakshminarayana, Colin Osborne, Jean-Rene Galarneau, Upendra Kulkarni, Wendy Richmond, Angela Bretz, Linda Xiao, Frantisek Supek, Christian Wiesmann, Srinivas Honnappa, Celine Be, Pascal Mäser, Marcel Kaiser, Ryan Ritchie, Michael P Barrett, Thierry T Diagana, Christopher Sarko, Srinivasa P S Rao. Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT). Journal of medicinal chemistry. 2022 Sep 08;65(17):11776-11787

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    PMID: 35993839

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