Webster Scott P, McBride Andrew, Binnie Margaret, Sooy Karen, Seckl Jonathan R, Andrew Ruth, Pallin T David, Hunt Hazel J, Perrior Trevor R, Ruffles Vincent S, Ketelbey J William, Boyd Alan, Walker Brian R
Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, UK.
Charles River Laboratories, Harlow, UK.
Br J Pharmacol. 2017 Mar;174(5):396-408. doi: 10.1111/bph.13699. Epub 2017 Jan 25.
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.
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.
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 t 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 IC .
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.
通过细胞内抑制皮质醇再生酶11β-羟基类固醇脱氢酶1型（11β-HSD1）来减少大脑中的糖皮质激素暴露，已成为治疗早期阿尔茨海默病（AD）认知障碍的一种治疗策略。我们试图发现新型的、可穿透大脑的11β-HSD1抑制剂，作为治疗AD的潜在药物。
对一系列酰胺基噻吩类似物进行药物化学优化，以鉴定出具有优化口服药代动力学且能够进入大脑的强效和选择性11β-HSD1抑制剂。在健康人类受试者中进行了单次和多次递增剂量研究，以确定候选化合物的安全性、药代动力学和药效学特征。
UE2343被鉴定为一种强效、口服生物可利用、可穿透大脑的11β-HSD1抑制剂，并被选用于临床研究。人类受试者未出现重大安全问题。在10毫克及以上剂量时，血浆促肾上腺皮质激素升高（全身酶抑制的标志物），但血浆皮质醇水平未改变。多次服用UE2343后，血浆水平大致与剂量成正比，终末半衰期为10至14小时。在10毫克及以上剂量时，尿中四氢皮质醇/四氢可的松比值降低，表明肝脏中11β-HSD1受到最大抑制。脑脊液中UE2343的浓度为游离血浆水平的33%，脑脊液中的峰值浓度比UE2343的IC高出九倍。
UE2343安全、耐受性良好，且能以预计可抑制11β-HSD1的浓度到达大脑。因此，UE2343是一个合适的候选药物，可用于检验大脑中11β-HSD1抑制可改善AD患者记忆力这一假设。
