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

Scott P Webster, Andrew McBride, Margaret Binnie, Karen Sooy, Jonathan R Seckl, Ruth Andrew, T David Pallin, Hazel J Hunt, Trevor R Perrior, Vincent S Ruffles, J William Ketelbey, Alan Boyd, Brian R Walker, Scott P Webster, Andrew McBride, Margaret Binnie, Karen Sooy, Jonathan R Seckl, Ruth Andrew, T David Pallin, Hazel J Hunt, Trevor R Perrior, Vincent S Ruffles, J William Ketelbey, Alan Boyd, Brian R Walker

Abstract

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. 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 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 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 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.

© 2016 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Figures

Figure 1
Figure 1
Lead structure and properties. Pharmacokinetics in rats was conducted by i.v. (n = 3 rats) and p.o. administration (n = 5 rats). The number of individual experiments [n] for measurement of in vitro human 11β‐HSD1 inhibition, plasma protein binding and aqueous solubility are shown. Data are reported as mean ± SD.
Figure 2
Figure 2
UE2343 concentrations following a single oral dose of UE2343. Six healthy male and two healthy female subjects per dose level.
Figure 3
Figure 3
Plasma ACTH following a single oral dose of UE2343. Six healthy male and two healthy female subjects per dose level. (A) ACTH levels up to 125 h post‐dose. (B) ACTH at 23 h post‐dose; ANOVA *P < 0.05.
Figure 4
Figure 4
Urinary THFs/THE ratios. (A) Effects on Day 1 following a single dose of UE2343; ANOVA *P < 0.05. Six healthy male and two healthy female subjects per dose level. (B) Effects up to Day 12 following multiple doses of UE2343; ANOVA, 10 (P < 0.05), 20 (P < 0.05) and 35 mg (P < 0.05). Eight healthy male subjects per dose level.
Figure 5
Figure 5
UE2343 levels in plasma and CSF following 4 days of administration of 35 mg b.i.d in four healthy male subjects.

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