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

Abstract

Background and PurposeReducing 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 ApproachMedicinal 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. Single and multiple ascending dose studies were conducted in healthy human subjects to determine the safety, pharmacokinetic and pharmacodynamic characteristics of the candidate compound.ResultsUE2343 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 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 t 1/2 ranged from 10 to 14 h. The urinary tetrahydrocortisols/tetrahydrocortisone ratio was reduced at doses of 10 mg and above, indicating maximal 11β‐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 ImplicationsUE2343 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.

High Cortisol and the Risk of Dementia and Alzheimer’s Disease: A Review of the Literature

“…Another potential mechanism by which cortisol effects can be reduced pharmacologically is the inhibition of cortisol synthesis, one of the key enzymes being the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Currently, a phase II trial of an 11β-HSD1 inhibitor (UE2343) as a potential treatment for AD is being conducted (Webster et al, 2017).…”

Quantification of 11β-hydroxysteroid dehydrogenase 1 kinetics and pharmacodynamic effects of inhibitors in brain using mass spectrometry imaging and stable-isotope tracers in mice

“…UE2316 is a brain-penetrant 11β-HSD1 inhibitor that is efficacious in preclinical models [24] and is chemically similar to UE2343, a clinical development candidate [11] to treat Alzheimer’s disease. It selectively inhibits the reductase activity of the enzyme.…”

“…Solvents were glass-distilled HPLC grade (Fisher Scientific, Loughborough, UK). UE2316, [4-(2-chlorophenyl)-4-fluoro-1-piperidinyl][5-(1 H -pyrazol-4-yl)-3-thienyl]-methanone and UE2346 [26] were synthesized by High Force Ltd, Durham, UK [11] . Other chemicals were from Sigma-Aldrich (Dorset, UK) unless stated.…”

“…In patients with Alzheimer’s disease, one study reported lack of efficacy of an 11β-HSD1 inhibitor but the data supporting pharmacodynamic engagement of the target in brain with this compound are contentious [10] . To justify progression of further candidate molecules for the treatment of dementia, such as UE2343 (Xanamem®) [11] , it would be important to demonstrate that 11β-HSD1 contributes substantially to glucocorticoid regeneration in relevant tissues in vivo, and that 11β-HSD1 inhibitors have pharmacodynamic effects in these tissues and brain sub-regions.…”

“…Pharmacodynamic assessment of 11β-HSD1 is challenging since circulating steroid concentrations do not reflect the local tissue levels. Although active glucocorticoid levels may be decreased in tissue following 11β-HSD1 inhibition, circulating levels are normalized by feedback control of the hypothalamic-pituitary-adrenal axis; this is a recognised response to enhanced cortisol clearance following inhibition of cortisol regeneration in humans, evident in compensatory increases in ACTH levels and circulating adrenal androgens [5] , [6] , [7] , [8] , [11] , [12] . Moreover, within the tissue pool of active endogenous steroid it is impossible to distinguish the proportion derived from the plasma pool from that regenerated intracellularly by 11β-HSD1.…”