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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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