biostudies-literatureKouridaki MEEuropean Research Council6815-6831https://www.ebi.ac.uk/biostudies/studies/S-EPMC11956012biostudies-literatureUnknown68(6)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 <b>1</b> 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 <b>11</b> is a potent cyclophilin B inhibitor with an encouraging pharmacokJournal of medicinal chemistryOptimization of Cyclophilin B-Targeted Tri-vector Inhibitors for Novel MASH Treatments.PMC11956012861942Robinson JMorrison AMathie TMaj KTurner DCameron KWebster SPHulme ANMichel JGreenslade DBDoughty-Shenton DKouridaki MEPapadourakis MWear MABain LGillespie JMcArthur DfalseOptimization 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 <b>1</b> 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 <b>11</b> is a potent cyclophilin B inhibitor with an encouraging pharmacok2025-01-01T00:00:00Z2025 Mar2026-06-02T17:30:25.324Z2025-06-25T03:04:28.032ZS-EPMC119560124007429110.1021/acs.jmedchem.5c00301