BACKGROUND AND PURPOSE: Reducing glucocorticoid exposure in the brain via intracellular inhibition of the cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase (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 optimisation of a series of amido-thiophene analogues was performed to identify potent and selective 11β-HSD1 inhibitors with optimised oral pharmacokinetics able to access the brain. Single and multiple ascending dose studies were conducted in healthy human subjects to determine the safety, pharmacokinetic and pharmacodynamic characteristics of the candidate compound.
RESULTS: UE2343 was identified as a potent, orally bioavailable, brain-penetrant 11β-HSD1 inhibitor and selected for clinical studies. No major safety issues occurred in human subjects. Plasma adrenocorticotropic hormone (ACTH) was elevated (a marker of systemic enzyme inhibition) at doses of 10mg and above, but plasma cortisol levels were unchanged. Following multiple doses of UE2343, plasma levels were approximately dose proportional and the terminal half-life ranged from 10-14h. The urinary tetrahydrocortisols (THFs)/tetrahydrocortisone (THE) ratio was reduced at doses of 10mg and above, indicating maximal 11β-HSD1 inhibition in the liver. Concentrations of UE2343 in the cerebrospinal fluid (CSF) were 33% of free plasma levels and the peak concentration in CSF was 9-fold greater than the UE2343 IC50 .
CONCLUSIONS AND IMPLICATIONS: UE2343 is safe, well tolerated and reaches the brain at concentrations predicted to inhibit 11β-HSD1. UE2343 is therefore a suitable candidate to test the hypothesis that 11β-HSD1 inhibition in brain improves memory in patients with AD.