Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore.

ABSTRACT: The mitochondrial permeability transition pore (mtPTP) is a Ca(2+) -requiring mega-channel which, under pathological conditions, leads to the deregulated release of Ca(2+) and mitochondrial dysfunction, ultimately resulting in cell death. Although the mtPTP is a potential therapeutic target for many human pathologies, its potential as a drug target is currently unrealized. Herein we describe an optimization effort initiated around hit 1, 5-(3-hydroxyphenyl)-N-(3,4,5-trimethoxyphenyl)isoxazole-3-carboxamide, which was found to possess promising inhibitory activity against mitochondrial swelling (EC50 <0.39 μM) and showed no interference on the inner mitochondrial membrane potential (rhodamine 123 uptake EC50 >100 μM). This enabled the construction of a series of picomolar mtPTP inhibitors t

SUBMITTER: Roy S 

PROVIDER: S-EPMC4674087 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature