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Second‐Generation Inhibitors of the Mitochondrial Permeability Transition Pore with Improved Plasma Stability
Author(s) -
Šileikytė Justina,
Devereaux Jordan,
Jong Jelle,
Schiavone Marco,
Jones Kristen,
Nilsen Aaron,
Bernardi Paolo,
Forte Michael,
Cohen Michael S.
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900376
Subject(s) - isoxazole , mitochondrial permeability transition pore , chemistry , in vivo , mitochondrion , click chemistry , inner mitochondrial membrane , oxidative phosphorylation , biophysics , stereochemistry , combinatorial chemistry , biochemistry , apoptosis , programmed cell death , biology , microbiology and biotechnology
Excessive mitochondrial matrix Ca 2+ 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)‐1 H ‐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.