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

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• 作者：James S. Scott ; Joanne deSchoolmeester ; Elaine Kilgour ; Rachel M. Mayers ; Martin J. Packer ; David Hargreaves ; Stefan Gerhardt ; Derek J. Ogg ; Amanda Rees ; Nidhal Selmi ; Andrew Stocker ; John G. Swales ; Paul R. O. Whittamore
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：10136-10147
• 全文大小：562K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

Inhibition of 11尾-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.