1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors
| Autor: | Paul Renton, Joanne Speed, Shawn Maddaford, Subhash C. Annedi, Jailall Ramnauth, Suman Rakhit, John Andrews |
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| Rok vydání: | 2011 |
| Předmět: |
Indoles
Dose-Response Relationship Drug Molecular Structure Organic Chemistry Clinical Biochemistry Pharmaceutical Science Stereoisomerism Nitric Oxide Synthase Type I Biochemistry Structure-Activity Relationship Drug Design Drug Discovery Humans Molecular Medicine Enzyme Inhibitors Molecular Biology |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 21:5301-5304 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2011.07.022 |
| Popis: | A series of 1,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase. A variety of flexible and restricted basic amine side chain substitutions was explored at the 1-position of the indole ring, while keeping the amidine group fixed at the 5-position. Compounds having N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)- (12, (R)-12, (S)-12 and 13) and N-(1-(1-methylazepan-4-yl)- side chains (14, 15, (-)-15 and (+)-15) showed increased inhibitory activity for the human nNOS isoform and selectivity over eNOS and iNOS isoforms. The most potent compound of the series for human nNOS (IC(50)=0.02 μM) (S)-12 showed very good selectivity over the eNOS (eNOS/nNOS=96-fold) and iNOS (iNOS/nNOS=850-fold) isoforms. |
| Databáze: | OpenAIRE |
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