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J Med Chem. 2009 Dec 24;52(24):7942-5. doi: 10.1021/jm901415x.

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

Author information

1
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. zaska@wyeth.com

Abstract

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 seen by creating a deeper pocket in mTOR that can accommodate bridged morpholines.

PMID:
19916508
DOI:
10.1021/jm901415x
[Indexed for MEDLINE]

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