Abstract
We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene displayed low nanomolar inhibition of 11β-HSD1. In continuation of our efforts to discover potent and selective 11β-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11β-HSD1, although with low selectivity over the isoenzyme 11β-HSD2, and poor microsomal stability.
Highlights
Glucocorticoids (GCs) are hormones that play a major role in the modulation of inflammatory and immune responses, metabolism regulation, cardiovascular homeostasis, and the body’s response to stress [1,2]
11β-HSD2 catalyzes the opposite reaction by oxidizing cortisol to cortisone [4]. 11β-HSD1 predominates in tissues mainly expressing glucocorticoids receptors, such as liver, adipose, and brain, whereas 11β-HSD2 is found in tissues mainly expressing mineralocorticoid receptors, such as kidney, colon, and salivary glands [5,6]
11β-HSD1 activity has been found to be important in type 2 diabetes and metabolic syndrome [8], in Alzheimer’s disease (AD) [9], in osteoporosis [10], and in glaucoma [11]
Summary
Glucocorticoids (GCs) are hormones that play a major role in the modulation of inflammatory and immune responses, metabolism regulation, cardiovascular homeostasis, and the body’s response to stress [1,2]. Selectivity against the desired 11β-HSD isoform is a key factor to avoid side effects of novel 11β-HSD1 inhibitors in development In recent years, both academia and industry have made great efforts to determine the role of this enzyme in diseases in which elevated cortisol plays an important role [7]. 11β-HSD1 activity has been found to be important in type 2 diabetes and metabolic syndrome [8], in Alzheimer’s disease (AD) [9], in osteoporosis [10], and in glaucoma [11] In light of this evidence, 11β-HSD1 has been explored as a therapeutic target to decrease cortisol concentrations in target tissues.
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