Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors.

@article{Zask2009MorpholineDG,
  title={Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors.},
  author={Arie Zask and Joshua Kaplan and Jeroen C Verheijen and David J Richard and Kevin J Curran and Natasja Brooijmans and Eric M. Bennett and Lourdes Toral-Barza and Irwin Hollander and Semiramis Ayral-Kaloustian and Ker Yu},
  journal={Journal of medicinal chemistry},
  year={2009},
  volume={52 24},
  pages={7942-5}
}
Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC(50) values and up to 26000-fold selectivity versus PI3Kalpha were prepared. Chiral morpholines gave inhibitors whose enantiomers had different selectivity and potency profiles. Molecular modeling suggests that a single amino acid difference between PI3K and mTOR (Phe961Leu) accounts for the profound selectivity… CONTINUE READING

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