Metabolic syndrome, also referred to as Syndrome X” or “Insulin Resistance Syndrome,” remains a major, unmet medical need despite over 30 years of intense effort. Recent research suggests that there may be a causal link between this condition and abnormal glucocorticoid processing. Specifically, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis leads to increased systemic cortisol concentrations. Cushing’ syndrome, a disorder that is also typified by a marked elevation in levels of cortisol, produces clinical symptomology that is similar to those observed in MetS, and they can be alleviated by decreasing circulating cortisol concentrations. As a result, it has been suggested that decreasing systemic cortisol concentration might have a positive impact on the progression of MetS. This could be accomplished through inhibition of enzymes in the cortisol synthetic pathway, 11β-hydroxylase (Cyp11B1), 17α-hydroxylase-C17,20-lyase (Cyp17), and 21-hydroxylase (Cyp21). We have identified a series of novel 5-(phenoxymethyl)-1,3-dioxanes that are potent inhibitors of these enzymes. In addition, our lead compound has pharmacokinetic properties consistent with orally delivered drugs, making it well suited to further investigation as a potential therapy for MetS.

Design, synthesis, and evaluation of functionalized 5-(phenoxymethyl)-1,3-dioxane analogs as potential treatments for metabolic syndrome

256th National Meeting (2018)

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