Small Molecule Inhibitors of Cyclophilin D To Protect Mitochondrial Function as a Potential Treatment for Acute Pancreatitis

Opening of the mitochondrial
permeability transition pore (MPTP)
causes mitochondrial dysfunction and necrosis in acute pancreatitis
(AP), a condition without specific drug treatment. Cyclophilin D (CypD)
is a mitochondrial matrix peptidyl-prolyl isomerase that regulates
the MPTP and is a drug target for AP. We have synthesized urea-based
small molecule inhibitors of cyclophilins and tested them against
CypD using binding and isomerase activity assays. Thermodynamic profiles
of the CypD/inhibitor interactions were determined by isothermal titration
calorimetry. Seven new high-resolution crystal structures of CypD–inhibitor
complexes were obtained to guide compound optimization. Compounds 4, 13, 14, and 19 were
tested in freshly isolated murine pancreatic acinar cells (PACs) to
determine inhibition of toxin-induced loss of mitochondrial membrane
potential (ΔΨm) and necrotic cell death pathway
activation. Compound 19 was found to have a Kd of 410 nM and a favorable thermodynamic profile, and it showed significant
protection of ΔΨm and reduced necrosis of murine
as well as human PACs. Compound 19 holds significant
promise for future lead optimization.