Dataset Information
Selection and early clinical evaluation of the brain-penetrant 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) inhibitor UE2343 (Xanamem™).
Ontology highlight
ABSTRACT: Background and purpose
Reducing glucocorticoid exposure in the brain via intracellular inhibition of the cortisol-regenerating enzyme 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) has emerged as a therapeutic strategy to treat cognitive impairment in early Alzheimer's disease (AD). We sought to discover novel, brain-penetrant 11?-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 11?-HSD1 inhibitors with optimized 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 11?-HSD1 inhibitor and selected for clinical studies. No major safety issues occurred in human subjects. Plasma adrenocorticotropic hormone was elevated (a marker of systemic enzyme inhibition) at doses of 10 mg and above, but plasma cortisol levels were unchanged. Following multiple doses of UE2343, plasma levels were approximately dose proportional and the terminal t1/2 ranged from 10 to 14 h. The urinary tetrahydrocortisols/tetrahydrocortisone ratio was reduced at doses of 10 mg and above, indicating maximal 11?-HSD1 inhibition in the liver. Concentrations of UE2343 in the CSF were 33% of free plasma levels, and the peak concentration in CSF was ninefold greater than the UE2343 IC50 .Conclusions and implications
UE2343 is safe, well tolerated and reaches the brain at concentrations predicted to inhibit 11?-HSD1. UE2343 is therefore a suitable candidate to test the hypothesis that 11?-HSD1 inhibition in brain improves memory in patients with AD.
SUBMITTER: Webster SP
PROVIDER: S-EPMC5301048 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
Publications
Selection and early clinical evaluation of the brain-penetrant 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (Xanamem™).
British journal of pharmacology 20170125 5
<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Medicinal chemistry optimization of a series of amido-thiophen ...[more]