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 <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 pharmacokinetic profile suitable for further development.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-03-12
DOI
https://doi.org/10.1021/acs.jmedchem.5c00301
Citations
2
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article
Field-Weighted Citation Impact
2.30
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article

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

Darryl Turner, K. Maj, Jonathan Gillespie, Duncan McArthur et al.
2 citations
Journal of Medicinal Chemistry
Endoplasmic Reticulum Stress and Disease
2.30
article

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

Darryl Turner, K. Maj, Jonathan Gillespie, Duncan McArthur, Scott P. Webster, Martin A. Wear, D. J. Greenslade, Tanya Mathie, Alison N. Hulme, Julien Michel, Michail Papadourakis, Angus J. Morrison, Luchuo Engelbert Bain, Dahlia Doughty-Shenton, Kate Cameron, John Robinson, Maria-Eleni Kouridaki
article en
2 citations

Abstract

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 pharmacokinetic profile suitable for further development.

Journal of Medicinal ChemistryVol. 68(6)
Scotland's Rural College (GB), NHS Lanarkshire (GB), Easterseals (US), MRC Centre for Regenerative Medicine (GB), MRC Centre for Reproductive Health (GB), Wellcome Centre for Cell Biology (GB), Concept Life Sciences (United Kingdom) (GB), The Queen's Medical Research Institute (GB), University of Edinburgh (GB)
Openalex Percentile: Top 15%
Endoplasmic Reticulum Stress and Disease
2.30
DOIOpen Access PDFOpenAlex
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