Discovery of Novel 2-Aniline-1,4-naphthoquinones as Potential New Drug Treatment for Leber's Hereditary Optic Neuropathy (LHON)
| Autor: | Charles Martin Heard, Andrea Brancale, Carmine Varricchio, Pascale Aeschlimann, Kathy Beirne, Marcela Votruba, Malgorzata Barbara Rozanowska |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Drug
Cell Survival media_common.quotation_subject Mitochondrial disease Optic Atrophy Hereditary Leber Pharmacology 01 natural sciences Optic neuropathy 03 medical and health sciences Mice Drug Discovery medicine NAD(P)H Dehydrogenase (Quinone) Idebenone Potency Animals Humans Mode of action 030304 developmental biology media_common 0303 health sciences Dose-Response Relationship Drug Chemistry Leber's hereditary optic neuropathy Hep G2 Cells medicine.disease 0104 chemical sciences Mice Inbred C57BL Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Treatment Outcome Pharmaceutical Preparations Molecular Medicine Female NAD+ kinase medicine.drug Naphthoquinones |
| Zdroj: | Journal of medicinal chemistry. 63(22) |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Leber’s hereditary optic neuropathy (LHON) is a rare genetic mitochondrial disease and the primary cause of chronic visual impairment for at least 1 in 10 000 individuals in the U.K. Treatment options remain limited, with only a few drug candidates and therapeutic approaches, either approved or in development. Recently, idebenone has been investigated as drug therapy in the treatment of LHON, although evidence for the efficacy of idebenone is limited in the literature. NAD(P)H:quinone oxidoreductase 1 (NQO1) and mitochondrial complex III were identified as the major enzymes involved in idebenone activity. Based on this mode of action, computer-aided techniques and structure–activity relationship (SAR) optimization studies led to the discovery of a series naphthoquinone-related small molecules, with comparable adenosine 5′-triphosphate (ATP) rescue activity to idebenone. Among these, three compounds showed activity in the nanomolar range and one, 2-((4-fluoro-3-(trifluoromethyl)phenyl)amino)-3-(methylthio)naphthalene-1,3-dione (1), demonstrated significantly higher potency ex vivo, and significantly lower cytotoxicity, than idebenone. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|