Identification of 4-N-2-(4-phenoxyphenyl)ethylquinazoline-46-diamine as a novel highly potent and specific inhibitor of mitochondrial complex I

摘要

By probing the quinone substrate binding site of mitochondrial complex I with a focused set of quinazoline-based compounds, we identified substitution patterns as being critical for the observed inhibition. The structure activity relationship study also resulted in the discovery of the quinazoline 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine (>EVP4593) as a highly potent inhibitor of the multisubunit membrane protein. >EVP4593 specifically and effectively reduces the mitochondrial complex I-dependent respiration with no effect on the respiratory chain complexes II–IV. Similar to established Q-site inhibitors, >EVP4593 elicits the release of reactive oxygen species at the flavin site of mitochondrial complex I. Recently, >EVP4593 was nominated as a lead compound for the treatment of Huntingtons disease. Our results challenge the postulated primary mode-of-action of >EVP4593 as an inhibitor of NF-κB pathway activation and/or store-operated calcium influx.