Discovery of 4-Morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as Highly Potent and Selective ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin (mTOR): Optimization of the

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• 作者：Jeroen C. Verheijen ; David J. Richard ; Kevin Curran ; Joshua Kaplan ; Mark Lefever ; Pawel Nowak ; David J. Malwitz ; Natasja Brooijmans ; Lourdes Toral-Barza ; Wei-Guo Zhang ; Judy Lucas ; Irwin Hollander ; Se
• 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：8010-8024
• 全文大小：1298K
• 年卷期：v.52,no.24(December 24, 2009)
• ISSN：1520-4804

文摘

Design and synthesis of a series of 4-morpholino-6-aryl-1H-pyrazolo[3,4-d]pyrimidines as potent and selective inhibitors of the mammalian target of rapamycin (mTOR) are described. Optimization of the 6-aryl substituent led to the discovery of inhibitors carrying 6-ureidophenyl groups, the first reported active site inhibitors of mTOR with subnanomolar inhibitory concentrations. The data presented in this paper show that 6-arylureidophenyl substituents led to potent mixed inhibitors of mTOR and phosphatidylinositol 3-kinase α (PI3K-α), whereas 6-alkylureidophenyl appendages gave highly selective mTOR inhibitors. Combination of 6-alkylureidophenyl groups with 1-carbamoylpiperidine substitution resulted in compounds with subnanomolar IC₅₀ against mTOR and greater than 1000-fold selectivity over PI3K-α. In addition, structure based drug design resulted in the preparation of several 6-arylureidophenyl-1H-pyrazolo[3,4-d]pyrimidines, substituted in the 4-position of the arylureido moiety with water solubilizing groups. These compounds combined potent mTOR inhibition (IC₅₀ < 1 nM) with unprecedented activity in cellular proliferation assays (IC₅₀ < 1 nM).