Sulfonyl-morpholino-pyrimidines: SAR and development of a novel class of selective mTOR kinase inhibitor

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• 作者：M. Raymond V. Finlay ; ^{ray.finlay@astrazeneca.com} ; David Buttar ; Susan E. Critchlow ; Allan P. Dishington ; Shaun M. Fillery ; Eric Fisher ; Steve C. Glossop ; Mark A. Graham ; Trevor Johnson ; Gillian M. Lamont ; Simon Mutton ; Paula Perkins ; Kurt G. Pike ; Anthony M. Slater.
• 关键词：Kinase ; Enzyme ; Inhibitor ; mTOR
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 June, 2012
• 卷：22
• 期：12
• 页码：4163-4168
• 文件大小：844 K

摘要

High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-pyrimidine rong class="boldFont">1rong> as an attractive start point. The compound displayed good physicochemical properties and selectivity over related kinases such as PI3K伪. Library preparation of related analogs allowed the establishment of additional SAR understanding and in particular the requirement for a key hydrogen bond donor motif at the 4-position of the phenyl ring in compounds such as indole rong class="boldFont">19rong>. Isosteric replacement of the indole functionality led to the identification of urea compounds such as rong class="boldFont">32rong> that show good levels of mTOR inhibition in both enzyme and cellular assays.