Optimization of Cyclophilin B‑Targeted Tri-vector Inhibitors for Novel MASH Treatments

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.