Morpholine Derivatives Greatly Enhance the Selectivity of Mammalian Target of Rapamycin (mTOR) Inhibitors

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• 作者：Arie Zask ; Joshua Kaplan ; Jeroen C. Verheijen ; David J. Richard ; Kevin Curran ; Natasja Brooijmans ; Eric M. Bennett ; Lourdes Toral-Barza ; Irwin Hollander ; Semiramis Ayral-Kaloustian ; Ker Yu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：December 24, 2009
• 年：2009
• 卷：52
• 期：24
• 页码：7942-7945
• 全文大小：776K
• 年卷期：v.52,no.24(December 24, 2009)
• ISSN：1520-4804

文摘

Dramatic improvements in mTOR-targeting selectivity were achieved by replacing morpholine in pyrazolopyrimidine inhibitors with bridged morpholines. Analogues with subnanomolar mTOR IC₅₀ values and up to 26000-fold selectivity versus PI3Kα 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.