11β-hydroxysteroid dehydrogenase type 1 inhibitor use in human disease-a systematic review and narrative synthesis.

Introduction: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an intracellular enzyme that catalyses conversion of cortisone into cortisol; correspondingly, 11β-HSD1 inhibitors inhibit this conversion. This systematic review focuses on the use of 11β-HSD1 inhibitors in diseases known to be associated with abnormalities in hypothalamic pituitary adrenal (HPA) axis function.

Methods: The databases screened for suitable papers were: MedLine, EMBASE, Web of Science, ClinicalTrials.

Selection and early clinical evaluation of the brain-penetrant 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (Xanamem™).

Background And Purpose: Reducing glucocorticoid exposure in the brain via intracellular inhibition of the cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has emerged as a therapeutic strategy to treat cognitive impairment in early Alzheimer's disease (AD). We sought to discover novel, brain-penetrant 11β-HSD1 inhibitors as potential medicines for the treatment of AD.

Experimental Approach: Medicinal chemistry optimization of a series of amido-thiophene analogues was performed to identify potent and selective 11β-HSD1 inhibitors with optimized oral pharmacokinetics able to access the brain.