Optimisation of pharmacokinetic properties in a neutral series of 11¦Â-HSD1 inhibitors
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- 作者：James S. Scott ; Adrian L. Gill ; Linda Godfrey ; Sam D. Groombridge ; Am ; a Rees ; John Revill ; Paul Schofield ; Pernilla S?rme ; Andrew Stocker ; John G. Swales ; Paul R.O. Whittamore
- 关键词：11¦Â-HSD1 inhibitors ; Pharmacokinetics ; Reactive metabolites
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：1 November, 2012
- 年：2012
- 卷：22
- 期：21
- 页码：6756-6761
- 全文大小：964 K
文摘
11¦Â-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11¦Â-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.