Krishnathas 2017 Med Chem Comm
| Krishnathas R, Bonke E, DrΓΆse S, Zickermann V, Nasiri HR (2017) Identification of 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine as a novel, highly potent and specific inhibitor of mitochondrial complex I. Med Chem Comm 8:657-61. |
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Krishnathas R, Bonke E, Droese S, Zickermann V, Nasiri HR (2017) Med Chem Comm
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 multisubunitmembrane protein. EVP4593 specifically and effectively reduces the mitochondrial complex I-dependent respiration with no effect on the respiratory chain complexes IIβIV. 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-ΞΊB pathway activation and/or store-operated calcium influx.
β’ Bioblast editor: Kandolf G β’ O2k-Network Lab: DE Frankfurt Droese S
Labels: MiParea: Respiration, Pharmacology;toxicology
Organism: Rat
Tissue;cell: Heart
Preparation: Isolated mitochondria
Regulation: Inhibitor Coupling state: OXPHOS Pathway: N, S HRR: Oxygraph-2k
