| Affiliation: | 1. Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239 USA;2. Medicinal Chemistry Core, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239 USA These authors contributed equally to this work.;3. Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy;4. Medicinal Chemistry Core, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239 USA;5. Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239 USA |
| 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, 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 nanomolar potency against mtPTP, they exhibited poor plasma stability, precluding their use in in vivo studies. Herein, we describe a series of structurally related analogues in which the core isoxazole was replaced with a triazole, which resulted in an improvement in plasma stability. These analogues were readily generated using the copper-catalyzed “click chemistry”. One analogue, N-(5-chloro-2-methylphenyl)-1-(4-fluoro-3-hydroxyphenyl)-1H-1,2,3-triazole-4-carboxamide ( TR001 ), was efficacious in a zebrafish model of muscular dystrophy that results from mtPTP dysfunction whereas the isoxazole isostere had minimal effect. |
