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

Authors
Journal
Bioorganic & Medicinal Chemistry Letters
0960-894X
Publisher
Elsevier
Publication Date
Volume
22
Issue
12
Identifiers
DOI: 10.1016/j.bmcl.2012.04.036
Keywords
  • Kinase
  • Enzyme
  • Inhibitor
  • Mtor
Disciplines
  • Biology
  • Chemistry

Abstract

Abstract High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-pyrimidine 1 as an attractive start point. The compound displayed good physicochemical properties and selectivity over related kinases such as PI3Kα. 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 19. Isosteric replacement of the indole functionality led to the identification of urea compounds such as 32 that show good levels of mTOR inhibition in both enzyme and cellular assays.

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