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. 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 IC50 values around 34–48 nm against human 11β-HSD1, display reasonable metabolic stability in human liver microsomes, and weak inhibition of key human CYP450 enzymes.
Highlights
Metabolic syndrome refers to a cluster of metabolic disorders, including insulin resistance, hyperglycemia, visceral obesity, hypertension and dyslipidemia
PF915275 (1; Figure 1), an inhibitor developed by Pfizer, has shown modest 11b-HSD1 inhibition in a clinical study.[38]
Results from a positive proof-of-concept clinical study of 11b-HSD1 inhibitor INCB013739, developed by Incyte, provide substantial evidence that inhibition of 11b-HSD1 can be a viable treatment of type 2 diabetes
Summary
Metabolic syndrome refers to a cluster of metabolic disorders, including insulin resistance, hyperglycemia, visceral obesity, hypertension and dyslipidemia. Combinations of these conditions represent major risk factors for developing cardiovascular disease and type 2 diabetes.[1,2] The rapid increase in the prevalence of cardiovascular disease and type 2 diabetes demands novel and effective approaches for the prevention and treatment of the syndrome. Previous studies have implicated excessive glucocorticoid action in the development of several phenotypes associated with metabolic syndrome.[3,4,5] Abnormal glucocorticoid receptor (GR) signalling is associated with insulin and leptin resistance, leading to the development of type 2 diabetes, obesity and cardiovascular disorders.[6,7] GR activation stimulates hepatic glucose production, antagonises insulin secretion from pancreatic b-cells and insulin-mediated glucose uptake in peripheral tissues,[8,9,10,11] and it promotes lipolysis and fatty acid mobilisation.[12]
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