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

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Awais, Muhammad, Woodley, Christopher M, Guo, Liqun, Rogers, Michael, Kershaw, Neil, Zacharchenko, Thomas, Shore, Emma, Kattakayam, Arjun, Mukherjee, Rajarshi ORCID: 0000-0003-0982-7883, Criddle, David N ORCID: 0000-0003-2952-8450 et al (show 9 more authors) , Leung, Suet C, Lee, Heather, Burgess-McCann, Joshua, Luzyanin, Konstantin ORCID: 0000-0001-9312-7139, Berry, Neil G ORCID: 0000-0003-1928-0738, Antonyuk, Svetlana ORCID: 0000-0002-2779-9946, Lian, Lu-Yun ORCID: 0000-0001-9481-749X, Sutton, Robert ORCID: 0000-0001-6600-562X and O'Neill, Paul M ORCID: 0000-0003-4338-0317 (2025) Potent Preorganized Pyrazolidine Cyclophilin D Inhibitors Prevent Mitochondrial and Organ Injury in a Mouse Pancreatitis Disease Model. Journal of medicinal chemistry, 68 (22). pp. 23910-23924. ISSN 0022-2623, 1520-4804

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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.

Item Type:	Article
Uncontrolled Keywords:	Mitochondria, Animals, Mice, Inbred C57BL, Humans, Mice, Pancreatitis, Disease Models, Animal, Pyrazoles, Cyclophilins, Mitochondrial Membrane Transport Proteins, Structure-Activity Relationship, Models, Molecular, Mitochondrial Permeability Transition Pore, Peptidyl-Prolyl Isomerase F
Divisions:	Faculty of Health & Life Sciences Faculty of Science & Engineering Faculty of Science & Engineering > School of Physical Sciences Faculty of Science & Engineering > School of Physical Sciences > Chemistry Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology (T&R Staff) Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Molecular & Clinical Cancer Medicine
Depositing User:	Symplectic Admin
Date Deposited:	11 Nov 2025 10:14
Last Modified:	09 Dec 2025 10:08
DOI:	10.1021/acs.jmedchem.5c01146
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3195312
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