Second generation inhibitors of the mitochondrial permeability transition pore with improved plasma stability.

Second generation inhibitors of the mitochondrial permeability transition pore with improved plasma stability. ChemMedChem. 2019 Aug 18;: Authors: Sileikyte J, Devereaux J, de Jong J, Schiavone M, Jones K, Nilsen A, Bernardi P, Forte M, Cohen M Abstract Excessive mitochondrial matrix Ca2+ and oxidative stress leads to the opening of a high-conductance channel of the inner mitochondrial membrane referred to as the mitochondrial permeability transition pore (mtPTP). Because mtPTP opening can lead to cell death under diverse pathophysiological conditions (e.g. ischemia-reperfusion injury and muscular dystrophy), inhibitors of mtPTP are potential therapeutics for various human diseases. High throughput screening efforts led to the identification of a 3-carboxamide-5-phenol-isoxazole compounds as mtPTP inhibitors. While they showed nM potency against mtPTP, they exhibited poor plasma stability, precluding their use in in vivo studies. Herein, we describe a series of structurally related analogs in which the core isoxazole was replaced with a triazole, and this replacement resulted in a substantial improvement in plasma stability. These analogs could be readily generated using the copper-catalyzed "click chemistry". One analog, TR001, was efficacious in a zebrafish model of muscular dystrophy that results from mtPTP dysfunction whereas the isoxazole isostere had minimal effect. PMID: 31423734 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research

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