Adamantyl ethanone pyridyl derivatives: potent and selective inhibitors of human 11 beta-hydroxysteroid dehydrogenase type 1

Xiangdong Su, Fabienne Pradaux-Caggiano, Nigel Vicker, Mark P. Thomas, Heather Halem, Michael D. Culler, Barry V. L. Potter

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Elevated levels of active glucocorticoids have been implicated in the development of several phenotypes of metabolic syndrome, such as type 2 diabetes and obesity. 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyses the intracellular conversion of inactive cortisone to cortisol. Selective 11 beta-HSD1 inhibitors have shown beneficial effects in various conditions, including diabetes, dyslipidemia and obesity. A series of adamantyl ethanone pyridyl derivatives has been identified, providing potent and selective inhibitors of human 11 beta-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11b-HSD1 and are selective for this isoform, with no activity against 11 beta-HSD2 and 17 beta-HSD1. Structure-activity relationship studies reveal that an unsubstituted pyridine tethered to an adamantyl ethanone motif through an ether or sulfoxide linker provides a suitable pharmacophore for activity. The most potent inhibitors have IC(50) values around 34-48 nm against human 11 beta-HSD1, display reasonable metabolic stability in human liver microsomes, and weak inhibition of key human CYP450 enzymes.
Original languageEnglish
Pages (from-to)1616-1629
JournalChemMedChem
Volume6
Issue number9
DOIs
Publication statusPublished - 5 Sep 2011

Keywords

  • diabetics
  • metabolic syndrome
  • inhibitors
  • adamantyl ethanones
  • hydroxysteroid dehydrogenases
  • 11 beta-HSD1

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