Journal of Medicinal Chemistry p. 8010 - 8024 (2009)
Update date:2022-08-05
Topics:
Verheijen, Jeroen C.
Richard, David J.
Curran, Kevin
Kaplan, Joshua
Lefever, Mark
Nowak, Pawel
Malwitz, David J.
Brooijmans, Natasja
Toral-Barza, Lourdes
Zhang, Wei-Guo
Lucas, Judy
Hollander, Irwin
Ayral-Kaloustian, Semiramis
Mansour, Tarek S.
Yu, Ker
Zask, Arie
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 (IC 50<1 nM). 2009 American Chemical Society.
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