Dataset Information

Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11?-Hydroxysteroid Dehydrogenase Type 1 (11?-HSD-1).

ABSTRACT: Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11?-hydroxysteroid dehydrogenase-type 1 (11?-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11?-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.

SUBMITTER: Li J

PROVIDER: S-EPMC4094253 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1).

Li Jun J Kennedy Lawrence J LJ Wang Haixia H Li James J JJ Walker Steven J SJ Hong Zhenqiu Z O'Connor Stephen P SP Nayeem Akbar A Camac Daniel M DM Morin Paul E PE Sheriff Steven S Wang Mengmeng M Harper Timothy T Golla Rajasree R Seethala Ramakrishna R Harrity Thomas T Ponticiello Randolph P RP Morgan Nathan N NN Taylor Joseph R JR Zebo Rachel R Gordon David A DA Robl Jeffrey A JA

ACS medicinal chemistry letters 20140522 7

Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11β-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientat ...[more]

PMID: 25050169

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Project description:The microsomal enzyme 11β-hydroxysteroid deydrogenase type 1 (11β-HSD1) catalyzes the interconversion of glucocorticoid receptor-inert cortisone to receptor- active cortisol, thereby acting as an intracellular switch for regulating the access of glucocorticoid hormones to the glucocorticoid receptor. There is strong evidence for an important aetiological role of 11β-HSD1 in various metabolic disorders including insulin resistance, diabetes type 2, hypertension, dyslipidemia and obesity. Hence, modulation of 11β-HSD1 activity with selective inhibitors is being pursued as a new therapeutic approach for the treatment of the metabolic syndrome. Since tea has been associated with health benefits for thousands of years, we sought to elucidate the active principle in tea with regard to diabetes type 2 prevention. Several teas and tea specific polyphenolic compounds were tested for their possible inhibition of cortisone reduction with human liver microsomes and purified human 11β-HSD1. Indeed we found that tea extracts inhibited 11β-HSD1 mediated cortisone reduction, where green tea exhibited the highest inhibitory potency with an IC50 value of 3.749 mg dried tea leaves per ml. Consequently, major polyphenolic compounds from green tea, in particular catechins were tested with the same systems. (-)-Epigallocatechin gallate (EGCG) revealed the highest inhibition of 11β-HSD1 activity (reduction: IC50 = 57.99 µM; oxidation: IC50 = 131.2 µM). Detailed kinetic studies indicate a direct competition mode of EGCG, with substrate and/or cofactor binding. Inhibition constants of EGCG on cortisone reduction were Ki = 22.68 µM for microsomes and Ki = 18.74 µM for purified 11β-HSD1. In silicio docking studies support the view that EGCG binds directly to the active site of 11β-HSD1 by forming a hydrogen bond with Lys187 of the catalytic triade. Our study is the first to provide evidence that the health benefits of green tea and its polyphenolic compounds may be attributed to an inhibition of the cortisol producing enzyme 11β-HSD1.

Dataset Information

Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11?-Hydroxysteroid Dehydrogenase Type 1 (11?-HSD-1).

Publications

Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD-1).

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