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. 2009 Dec 24;52(24):8010-24.
doi: 10.1021/jm9013828.

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 6-aryl substituent

Jeroen C Verheijen  1 , 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, Semiramis Ayral-Kaloustian, Tarek S Mansour, Ker Yu, Arie Zask
Affiliations

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 6-aryl substituent

Jeroen C Verheijen et al. J Med Chem. .

Abstract

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 alpha (PI3K-alpha), whereas 6-alkylureidophenyl appendages gave highly selective mTOR inhibitors. Combination of 6-alkylureidophenyl groups with 1-carbamoylpiperidine substitution resulted in compounds with subnanomolar IC(50) against mTOR and greater than 1000-fold selectivity over PI3K-alpha. 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 (IC(50) < 1 nM) with unprecedented activity in cellular proliferation assays (IC(50) < 1 nM).

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