Optimization of 1,2,4-Triazolopyridines as Inhibitors of Human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-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 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 orientation of this TZP series was revealed by X-ray crystallography structure studies.

Clinical significance of CYP2C19 polymorphisms on the metabolism and pharmacokinetics of 11β‐hydroxysteroid dehydrogenase type‐1 inhibitor BMS‐823778

“…BMS‐823778 is a potent, selective, competitive and fully reversible inhibitor of human 11β‐HSD1 . Cell free biochemical assays showed that BMS‐823778 was more potent against human 11β‐HSD1 than the animal isoforms, and was 10 000‐fold selective for human 11β‐HSD1 over 11β‐HSD2.…”

The syntheses of [13C6] and [phenyl‐14C(U)]BMS‐816336, an inhibitor of 11β‐hydroxysteroid dehydrogenase type 1, for type 2 diabetes

“…11β‐HSD1 knockout mice were found to be resistant to obesity and hyperglycemia. Therefore, it would seem that an inhibitor of 11β‐HSD1 could possibly be an efficacious therapy for the treatment of dysmetabolic syndrome and type 2 diabetes . BMS‐816336, as shown in Figure , represents such an 11β‐HSD1 inhibitor .…”

“…Therefore, it would seem that an inhibitor of 11β-HSD1 could possibly be an efficacious therapy for the treatment of dysmetabolic syndrome and type 2 diabetes. [3][4][5] BMS-816336, as shown in Figure 1, represents such an 11β-HSD1 inhibitor. [6][7][8][9] To further the development of BMS-816336, it was necessary to prepare [phenyl-14 C(U)] BMS-816336 for metabolic profiling and stable-isotope labeled BMS-816336 for use as a liquid chromatography/ mass spectrometry (LC/MS) standard.…”

A validated enantioselective LC–MS/MS assay for quantification of a major chiral metabolite of an achiral 11-β-hydroxysteroid-dehydrogenase 1 inhibitor in human plasma: Application to a clinical pharmacokinetic study

“…823778 (Fig. 1A) is a novel, potent, orally administered 11␤HSD-1 inhibitor [6,7]. Data from in vitro studies and early clinical studies indicate that BMS-823778, a prochiral molecule, is metabolized by human liver enzyme Cytochrome P450 2C19 (CYP2C19) to a chiral hydroxy metabolite (BMT-094817- Fig.…”