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Adamantyl Ethanone Pyridyl Derivatives: Potent and Selective Inhibitors of Human 11β‐Hydroxysteroid Dehydrogenase Type 1
Author(s) -
Su Xiangdong,
PradauxCaggiano Fabienne,
Vicker Nigel,
Thomas Mark P.,
Halem Heather,
Culler Michael D.,
Potter Barry V. L.
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100182
Subject(s) - chemistry , 11β hydroxysteroid dehydrogenase type 1 , pharmacophore , enzyme , ether , dyslipidemia , alcohol dehydrogenase , dehydrogenase , cortisone , biochemistry , stereochemistry , pharmacology , diabetes mellitus , endocrinology , biology , organic chemistry
Elevated levels of active glucocorticoids have been implicated in the development of several phenotypes of metabolic syndrome, such as type 2 diabetes and obesity. 11β‐Hydroxysteroid dehydrogenase type 1 (11β‐HSD1) catalyses the intracellular conversion of inactive cortisone to cortisol. Selective 11β‐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 11β‐HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11β‐HSD1 and are selective for this isoform, with no activity against 11β‐HSD2 and 17β‐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 n M against human 11β‐HSD1, display reasonable metabolic stability in human liver microsomes, and weak inhibition of key human CYP450 enzymes.