Journal of Medicinal Chemistry p. 2596 - 2611 (2016)
Update date:2022-08-15
Topics:
Shore, Emma R.
Awais, Muhammad
Kershaw, Neil M.
Gibson, Robert R.
Pandalaneni, Sravan
Latawiec, Diane
Wen, Li
Javed, Muhammad A.
Criddle, David N.
Berry, Neil
O'Neill, Paul M.
Lian, Lu-Yun
Sutton, Robert
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.
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