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
- 出版时间：15 June, 2012
- 年：2012
- 卷：22
- 期：12
- 页码：4163-4168
- 全文大小：844 K
文摘
High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-pyrimidine class=""boldFont"">1 as an attractive start point. The compound displayed good physicochemical properties and selectivity over related kinases such as PI3K¦Á. 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 class=""boldFont"">19. Isosteric replacement of the indole functionality led to the identification of urea compounds such as class=""boldFont"">32 that show good levels of mTOR inhibition in both enzyme and cellular assays.