Novel Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4-[4-(2-Adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic Acid (AZD8329)

被引：35

作者：

Scott, James S. ^{[1
]}

deSchoolmeester, Joanne ^{[1
]}

Kilgour, Elaine ^{[1
]}

Mayers, Rachel M. ^{[1
]}

Packer, Martin J. ^{[1
]}

Hargreaves, David ^{[1
]}

Gerhardt, Stefan ^{[1
]}

Ogg, Derek J. ^{[1
]}

Rees, Amanda ^{[1
]}

Selmi, Nidhal ^{[1
]}

Stocker, Andrew ^{[1
]}

Swales, John G. ^{[1
]}

Whittamore, Paul R. O. ^{[1
]}

机构：

[1] AstraZeneca Mereside, Cardiovasc & Gastrointestinal Innovat Med Unit, Macclesfield SK10 4TG, Cheshire, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 22期

关键词：

D O I：

10.1021/jm301252n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of 11 beta-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.

引用

页码：10136 / 10147

页数：12

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