Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): Optimization of the 1-substituent Academic Article uri icon

Overview

MeSH Major

  • Adenosine Triphosphate
  • Intracellular Signaling Peptides and Proteins
  • Protein-Serine-Threonine Kinases
  • Pyrazoles
  • Pyridines

abstract

  • A series of pyrazolopyrimidine mammalian Target Of Rapamycin (mTOR) inhibitors with various substituents at the 1-position have been prepared, resulting in compounds with excellent potency, selectivity and microsomal stability. Combination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8h following iv administration and showed excellent oral activity in a xenograft tumor model.

publication date

  • February 15, 2010

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1016/j.bmcl.2009.12.086

PubMed ID

  • 20089401

Additional Document Info

start page

  • 1440

end page

  • 4

volume

  • 20

number

  • 4