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Identification of 4- N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine as a novel, highly potent and specific inhibitor of mitochondrial complex I

Identification of 4- N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine as a novel, highly potent and specific inhibitor of mitochondrial complex I

Robin Krishnathas, Erik Bonke, Stefan Dröse, Volker Zickermann, Hamid R Nasiri

Medchemcomm. 2017 Feb 20;8(3):657-661.

PMID: 30108783

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP111961876	N,N,N′,N′-Tetraphenylnaphthalene-2,6-diamine		111961-87-6	Price
AP545380345	EVP4593		545380-34-5	Price

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