Potent Preorganized Pyrazolidine Cyclophilin D Inhibitors Prevent Mitochondrial and Organ Injury in a Mouse Pancreatitis Disease Model
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 <i>cis</i>-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 <i>in vitro</i>. <i>In vivo</i>, <b>18f</b> provided a significant improvement of acute pancreatitis biomarkers in the CER-AP mouse pancreatitis model, underlining the potential of this series.
Authors
- Suet C. Leung
- Konstantin V. Luzyanin (ORCID: https://orcid.org/0000-0001-9312-7139)
- Michael S. Rogers (ORCID: https://orcid.org/0000-0002-5250-8434)
- Neil G. Berry (ORCID: https://orcid.org/0000-0003-1928-0738)
- Neil M. Kershaw (ORCID: https://orcid.org/0000-0002-4557-1742)
- Paul M. O’Neill (ORCID: https://orcid.org/0000-0003-4338-0317)
- Rajarshi Mukherjee (ORCID: https://orcid.org/0000-0003-0982-7883)
- Muhammad Awais (ORCID: https://orcid.org/0000-0003-2170-5344)
- S.V. Antonyuk (ORCID: https://orcid.org/0000-0002-2779-9946)
- Heather Lee (ORCID: https://orcid.org/0000-0002-6482-0337)
- David N. Criddle (ORCID: https://orcid.org/0000-0003-2952-8450)
- Thomas Zacharchenko (ORCID: https://orcid.org/0000-0001-5621-8605)
- Christopher M. Woodley (ORCID: https://orcid.org/0000-0003-1311-4288)
- Lu‐Yun Lian (ORCID: https://orcid.org/0000-0001-9481-749X)
- Robert Sutton (ORCID: https://orcid.org/0000-0001-6600-562X)
- Emma R. Shore
- Arjun Kattakayam
- Liqun Guo
- Joshua Burgess-McCann
Institutions
- University of Liverpool (GB)
- Aintree University Hospitals NHS Foundation Trust (GB)
- Wellcome Centre for Cell-Matrix Research (GB)
- NIHR Liverpool Pancreatic Biomedical Research Unit (GB)
- Integrative Medicine Institute (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-10
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01146
- Citations
- 1
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.81