Generation of 3,8-substituted 1,2,4-triazolopyridines as potent inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1)

Haixia Wang; Jeffrey A Robl; Lawrence G Hamann; Ligaya Simpkins; Rajasree Golla; Yi-Xin Li; Ramakrishna Seethala; Tatyana Zvyaga; David A Gordon; James J Li

doi:10.1016/j.bmcl.2011.05.101

Generation of 3,8-substituted 1,2,4-triazolopyridines as potent inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1)

Bioorg Med Chem Lett. 2011 Jul 15;21(14):4146-9. doi: 10.1016/j.bmcl.2011.05.101.

Authors

Haixia Wang¹, Jeffrey A Robl, Lawrence G Hamann, Ligaya Simpkins, Rajasree Golla, Yi-Xin Li, Ramakrishna Seethala, Tatyana Zvyaga, David A Gordon, James J Li

Affiliation

¹ Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543, USA.

PMID: 21689935
DOI: 10.1016/j.bmcl.2011.05.101

Abstract

A series of pyridyl amide/sulfonamide inhibitors of 11β-HSD-1 were modified to incorporate a novel 1,2,4-triazolopyridine scaffold. Optimization of substituents at the 3 and 8 position of the TZP core, with a special focus on enhancing metabolic stability, resulted in the identification of compound 38 as a potent and metabolically stable inhibitor of the enzyme.

MeSH terms

11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology
Humans
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology
Structure-Activity Relationship
Triazoles / chemical synthesis
Triazoles / chemistry*
Triazoles / pharmacology

Substances

Enzyme Inhibitors
Pyridines
Pyrimidines
Triazoles
1,2,4-triazole
11-beta-Hydroxysteroid Dehydrogenase Type 1