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Lookup NU author(s): Professor Brian WalkerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2016 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.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 t1/2ranged 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.
Author(s): Webster SP, McBride A, Binnie M, Sooy K, Seckl JR, Andrew R, Pallin TD, Hunt HJ, Perrior TR, Ruffles VS, Ketelbey JW, Boyd A, Walker BR
Publication type: Article
Publication status: Published
Journal: British Journal of Pharmacology
Year: 2017
Volume: 174
Issue: 5
Pages: 396-408
Print publication date: 01/03/2017
Online publication date: 23/12/2016
Acceptance date: 15/12/2016
Date deposited: 22/12/2017
ISSN (print): 0007-1188
ISSN (electronic): 1476-5381
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.1111/bph.13699
DOI: 10.1111/bph.13699
PubMed id: 28012176
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