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

  • J Med Chem. 2025 Mar 27;68(6):6815-6831. doi: 10.1021/acs.jmedchem.5c00301.
Maria-Eleni Kouridaki  1 ,  Jonathan Gillespie  2 ,  John Robinson  2 ,  Tanya Mathie  2 ,  Laura Bain  2 ,  Duncan McArthur  2 ,  Angus Morrison  2 ,  Daniel B Greenslade  1 ,  Michail Papadourakis  1 ,  Kasia Maj  3 ,  Kate Cameron  3 ,  Darryl Turner  4 ,  Scott P Webster  5 ,  Martin A Wear  6 ,  Dahlia Doughty-Shenton  7 ,  Alison N Hulme  1 ,  Julien Michel  1
Affiliations
  • 1. EaStCHEM School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh, Scotland EH9 3FJ, U.K.
  • 2. BioAscent Discovery Ltd., Newhouse, Scotland Lanarkshire ML1 5UH, U.K.
  • 3. Cytochroma Ltd., Roslin Innovation Centre, Easter Bush Estate, Edinburgh, Scotland EH25 9RG, U.K.
  • 4. Concept Life Sciences Ltd., Nine, 9 Little France Road, Edinburgh Bioquarter, Edinburgh, Scotland EH16 4UX, U.K.
  • 5. Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, Scotland EH16 4TJ, U.K.
  • 6. The Edinburgh Protein Production Facility (EPPF), University of Edinburgh, Level 3 Michael Swann Building, King's Buildings, Max Born Crescent, Edinburgh, Scotland EH9 3FF, U.K.
  • 7. Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, 4-5 Little France Drive, Edinburgh Bioquarter, Edinburgh, Scotland EH16 4UU, U.K.
PMID: 40074291 DOI: 10.1021/acs.jmedchem.5c00301
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 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.

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