Discovery of a Potent, Selective, and Orally Bioavailable Acidic 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitor: Discovery of 2-[(3S)-1[5-(Cyclohexylcarbamoyl)-6-propylsulfanylpyridin-2-yl]-3-piperidyl]acetic Acid (AZD4017)

被引：52

作者：

Scott, James S. ^{[1
]}

Bowker, Suzanne S. ^{[1
]}

deschoolmeester, Joanne ^{[1
]}

Gerhardt, Stefan ^{[1
]}

Hargreaves, David ^{[1
]}

Kilgour, Elaine ^{[1
]}

Lloyd, Adele ^{[1
]}

Mayers, Rachel M. ^{[1
]}

McCoull, William ^{[1
]}

Newcombe, Nicholas J. ^{[1
]}

Ogg, Derek ^{[1
]}

Packer, Martin J. ^{[1
]}

Rees, Amanda ^{[1
]}

Revill, John ^{[1
]}

Schofield, Paul ^{[1
]}

Selmi, Nidhal ^{[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 / 12期

关键词：

DIABETES-MELLITUS; METABOLIC SYNDROME; HYPERTENSION; 1-AMINOBENZOTRIAZOLE; CLEARANCE; CHEMISTRY; CORTISOL; MK-0916; OBESITY; LACKING;

D O I：

10.1021/jm300592r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of 11 beta-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11 beta-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.

引用

页码：5951 / 5964

页数：14

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