Abstract
CYP11B2 inhibition is a promising treatment for diseases caused by excessive aldosterone. To improve the metabolic stability in human liver miscrosomes of previously reported CYP11B2 inhibitors, modifications were performed via a combination of ligand- and structure-based drug design approaches, leading to pyridyl 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolones. Compound 26 not only exhibited a much longer half-life (t1/2 ≫ 120 min), but also sustained inhibitory potency (IC50 = 4.2 nM) and selectivity over CYP11B1 (SF = 422), CYP17, CYP19, and a panel of hepatic CYP enzymes.
MeSH terms
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Aldosterone / metabolism
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Aromatase / chemistry*
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Aromatase / metabolism
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Cytochrome P-450 CYP11B2 / antagonists & inhibitors
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Cytochrome P-450 CYP11B2 / metabolism
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Drug Design
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Humans
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In Vitro Techniques
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Microsomes, Liver / drug effects*
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Models, Molecular
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Molecular Structure
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Quinolines / chemistry*
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Quinolines / pharmacology*
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Steroid 11-beta-Hydroxylase / antagonists & inhibitors*
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Steroid 11-beta-Hydroxylase / metabolism
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Steroid 17-alpha-Hydroxylase / antagonists & inhibitors*
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Steroid 17-alpha-Hydroxylase / metabolism
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Structure-Activity Relationship
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Substrate Specificity
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Triazoles / chemistry*
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Triazoles / pharmacology*
Substances
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9-fluoro-1-methyl-7-(4-methylpyridin-3-yl)-4,5-dihydro(1,2,4)triazolo(4,3-a)quinoline
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Enzyme Inhibitors
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Quinolines
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Triazoles
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Aldosterone
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Aromatase
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Steroid 17-alpha-Hydroxylase
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Cytochrome P-450 CYP11B2
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Steroid 11-beta-Hydroxylase