Journal of medicinal chemistry · 2025
Optimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments.
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Kouridaki Maria-Eleni, Gillespie Jonathan, Robinson John, Mathie Tanya, Bain Laura, McArthur Duncan, Morrison Angus, Greenslade Daniel B, Papadourakis Michail, Maj Kasia, Cameron Kate, Turner Darryl, Webster Scott P, Wear Martin A, Doughty-Shenton Dahlia, Hulme Alison N, Michel Julien
Аннотация
Cyclophilins have been implicated in the pathophysiology of metabolic dysfunction-associated steatohepatitis (MASH). Pharmacological inhibition of the cyclophilin B isoform has the potential to attenuate liver fibrosis in MASH, but current cyclophilin inhibitors in clinical trials lack isoform selectivity. We previously reported the novel tri-vector small-molecule inhibitor 1 that exhibited improved subtype selectivity by simultaneously engaging three pockets on the surface of cyclophilins. Here, we present structure-activity relationships that address genotoxicity concerns, enhance subtype selectivity, improve pharmaceutical properties, and demonstrate strong efficacy in a MASH cellular model. Lead compound 11 is a potent cyclophilin B inhibitor with an encouraging pharmacokinetic profile suitable for further development.