Substituted indoles as potent and orally active 5-lipoxygenase activating protein (FLAP) inhibitors
| Autor: | Diane Ethier, Philip Tagari, Richard Frenette, H. Piechuta, C. C. Chan, Denis Riendeau, Michel Therien, M. McAuliffe, Yves Girard, John H. Hutchinson, Christine Brideau, Stella Charleson, Thomas R. Jones, Jocelyne Guay, Serge Leger |
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| Rok vydání: | 1999 |
| Předmět: |
Indoles
Stereochemistry 5-Lipoxygenase-Activating Proteins Clinical Biochemistry Pharmaceutical Science In Vitro Techniques Biochemistry Leukotriene biosynthesis Structure-Activity Relationship chemistry.chemical_compound Dogs Drug Discovery Animals Humans Moiety Lipoxygenase Inhibitors 5-lipoxygenase-activating protein Molecular Biology Indole test biology Organic Chemistry Quinoline Membrane Proteins Rats Orally active chemistry Quinolines biology.protein Molecular Medicine Carrier Proteins |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 9:2391-2396 |
| ISSN: | 0960-894X |
| Popis: | This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. Lead optimization culminated in (3-[1-(4-chlorobenzyl)-3-( t -butylthio)-5-(pyridin-2-ylmethoxy)-indol-2-yl]-2,2-dimethylpropanoic acid ( 18k ), as a potent inhibitor of leukotriene biosynthesis that is well absorbed and active in functional models. This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. A potent inhibitor, which is well absorbed and active in functional models, was identified. |
| Databáze: | OpenAIRE |
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