- Rational Design of Potent and Selective Inhibitors of an Epoxide Hydrolase Virulence Factor from Pseudomonas aeruginosa
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The virulence factor cystic fibrosis transmembrane conductance regulator (CFTR) inhibitory factor (Cif) is secreted by Pseudomonas aeruginosa and is the founding member of a distinct class of epoxide hydrolases (EHs) that triggers the catalysis-dependent
- Kitamura, Seiya,Hvorecny, Kelli L.,Niu, Jun,Hammock, Bruce D.,Madden, Dean R.,Morisseau, Christophe
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supporting information
p. 4790 - 4799
(2016/06/13)
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- 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
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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 (IC50501 nM). 2009 American Chemical Society.
- 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
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supporting information; experimental part
p. 8010 - 8024
(2010/07/04)
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- NOVEL BIPHENYL COMPOUNDS AND THEIR USE
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The invention is directed to certain biphenyl compounds. Specifically, the invention is directed to compounds according to Formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and Y are as defined below, and to pharmaceutically-acceptable salts thereo
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Page/Page column 45
(2010/10/20)
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