Discovery of Adamantyl Heterocyclic Ketones as Potent 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors

被引：8
|
作者：
Su, Xiangdong [1 ]
Vicker, Nigel [1 ]
Thomas, Mark P. [1 ]
Pradaux-Caggiano, Fabienne [1 ]
Halem, Heather [2 ]
Culler, Michael D. [2 ]
Potter, Barry V. L. [1 ]
机构：
[1] Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England
[2] Biomeasure Inc, IPSEN, Milford, MA 01757 USA
来源：
CHEMMEDCHEM | 2011年 / 6卷 / 08期
基金：
英国惠康基金;
关键词：
11; beta-HSD1; inhibitors; adamantyl ethanones; diabetes; hydroxysteroid dehydrogenases; metabolic syndrome; HEPATIC INSULIN SENSITIVITY; SELECTIVE INHIBITORS; ADIPOSE-TISSUE; CUSHINGS-SYNDROME; VISCERAL OBESITY; BLOOD-PRESSURE; 11-BETA-HSD1; CORTISOL; TRIAZOLES; DISEASE;
D O I：
10.1002/cmdc.201100144
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) plays a key role in converting intracellular cortisone to physiologically active cortisol, which is implicated in the development of several phenotypes of metabolic syndrome. Inhibition of 11 beta-HSD1 activity with selective inhibitors has beneficial effects on various conditions, including diabetes, dyslipidemia and obesity, and therefore constitutes a promising strategy to discover novel therapies for metabolic and cardiovascular diseases. A series of novel adamantyl heterocyclic ketones provides potent and selective inhibitors of human 11 beta-HSD1. Lead compounds display low nanomolar inhibition against human and mouse 11 beta-HSD1 and are selective with no activity against 11 beta-HSD2 and 17 beta-HSD1. Selected potent 11 beta-HSD1 inhibitors show moderate metabolic stability upon incubation with human liver microsomes and weak inhibition of human CYP450 enzymes.
引用
收藏
页码：1439 / 1451
页数：13
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