2. Academic Validation
  3. Potent Preorganized Pyrazolidine Cyclophilin D Inhibitors Prevent Mitochondrial and Organ Injury in a Mouse Pancreatitis Disease Model

Potent Preorganized Pyrazolidine Cyclophilin D Inhibitors Prevent Mitochondrial and Organ Injury in a Mouse Pancreatitis Disease Model

  • J Med Chem. 2025 Nov 27;68(22):23910-23924. doi: 10.1021/acs.jmedchem.5c01146.
Muhammad Awais 1,  Christopher M Woodley 2,  Liqun Guo 2,  Michael Rogers 2,  Neil Kershaw 2,  Thomas Zacharchenko 3,  Emma Shore 2,  Arjun Kattakayam 1 4,  Rajarshi Mukherjee 1 5 4,  David N Criddle 1,  Suet C Leung 2,  Heather Lee 2,  Joshua Burgess-McCann 2,  Konstantin Luzyanin 2,  Neil G Berry 2,  Svetlana Antonyuk 1,  Lu-Yun Lian 1,  Robert Sutton 1 4,  Paul M O'Neill 2
Affiliations

Affiliations

  • 1 Department of Molecular and Clinical Cancer Medicine, Liverpool Pancreatitis Research Group, University of Liverpool, Liverpool L69 7BE, U.K.
  • 2 Robert Robinson Laboratories, University of Liverpool, Chemistry, Oxford Street, Liverpool L69 7ZD, U.K.
  • 3 Wellcome Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building Dover Street, Manchester M13 9PT, U.K.
  • 4 Liverpool University Hospitals NHS Foundation Trust, Liverpool L7 8XP, U.K.
  • 5 Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7GE, U.K.
PMID: 41208336 DOI: 10.1021/acs.jmedchem.5c01146
Abstract

Cyclophilin D inhibitors that prevent opening of the mitochondrial permeability transition pore (MPTP) are potential treatments for a range of acute and chronic diseases, including acute pancreatitis. Here, we report that replacement of carbon with nitrogen in the pyrrolidine headgroup of a series of Cyclophilin D inhibitors gives a dramatic enhancement in binding affinity (>40 fold), and prolyl isomerase inhibition (PPIase) activity (>200 fold), which is ascribed to a preorganization of the pyrazolidine amide headgroup. Protein-ligand X-ray crystal structures and NMR and molecular modeling demonstrate the importance of cis-amide geometry within the preorganized conformation, ensuring the ligand headgroup is anchored in the S1' binding pocket, leading to potent nM PPIase inhibition and binding. Pyrazolidines potently inhibit MPTP opening and prevent pancreatic toxin-induced cell necrosis in vitro. In vivo, 18f provided a significant improvement of acute pancreatitis biomarkers in the CER-AP mouse pancreatitis model, underlining the potential of this series.

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