- Discovery of potent and selective inhibitors of the mammalian target of rapamycin (mTOR) kinase
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The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. High throughput screening (HTS) of our compound collection led to the identification of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)phenol (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model based on an X-ray crystal structure of closely related PI3Kγ led to the discovery of 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1- (pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (5u), a potent and selective mTOR inhibitor (mTOR IC50 = 9 nM; PI3Kα IC 50 = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORC1 (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy. 2009 American Chemical Society.
- Nowak, Pawel,Cole, Derek C.,Brooijmans, Natasja,Bursavich, Matthew G.,Curran, Kevin J.,Ellingboe, John W.,Gibbons, James J.,Hollander, Irwin,Hu, YongBo,Kaplan, Joshua,Malwitz, David J.,Toral-Barza, Lourdes,Verheijen, Jeroen C.,Zask, Arie,Zhang, Wei-Guo,Yu, Ker
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experimental part
p. 7081 - 7089
(2010/04/29)
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- CHEMICAL COMPOUNDS
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The present invention provides compounds of formula (I) wherein R1, R2, R3, R4, Het and m are as defined in the description. The compounds of the present invention are modulators, especially antagonists, of the
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Page/Page column 29
(2009/09/05)
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- ATP-competitive inhibitors of the mammalian target of rapamycin: Design and synthesis of highly potent and selective pyrazolopyrimidines
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The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.
- Zask, Arie,Verheijen, Jeroen C.,Curran, Kevin,Kaplan, Joshua,Richard, David J.,Nowak, Pawel,Malwitz, David J.,Brooijmans, Natasja,Bard, Joel,Svenson, Kristine,Lucas, Judy,Toral-Barza, Lourdes,Zhang, Wei-Guo,Hollander, Irwin,Gibbons, James J.,Abraham, Robert T.,Ayral-Kaloustian, Semiramis,Mansour, Tarek S.,Yu, Ker
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supporting information; experimental part
p. 5013 - 5016
(2010/03/04)
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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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experimental part
p. 8010 - 8024
(2010/07/04)
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- THIENOPYRIMIDINE AND PYRAZOLOPYRIMIDINE COMPOUNDS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS
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The invention relates to thienopyrimidine and pyrazolopyrimidine compounds of the Formulas (Ia) and (IIa), or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein compositions comprising the compounds, and methods for making and using the compounds.
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Page/Page column 59
(2009/04/24)
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- PYRAZOLOPYRIMIDINE ANALOGS AND THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS
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The present invention relates to Pyrazolopyrimidine Analogs, methods of making Pyrazolopyrimidine Analogs, compositions comprising a Pyrazolopyrimidine Analog, and methods for treating mTOR-related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog. The invention also relates to treating PI3K-related disorders comprising administering to a subject in need thereof an effective amount of a Pyrazolopyrimidine Analog.
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Page/Page column 84
(2008/12/08)
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- TRIAZOLYLPIPERIDINE DERIVATIVES AND USE THEREOF IN THERAPY
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The present invention provides compounds of formula (I) Wherein R1 , R2, R3 , R4 , Het and m are as defined in the description. The compounds of the present invention are modulators, especially antagonists, of the activity of chemokine CCR5 receptors.
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Page/Page column 29
(2010/11/25)
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- SULFONYLUREIDOPYRAZOLE DERIVATIVES
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A sulfonylureidopyrazole derivative of formula (1) or (2) is disclosed. The derivative has an inhibitory activity on endothelin converting enzyme, and is useful for treating or preventing various cardiac failures, tracheal constrictions, nervous disorders, parasecretion, vascular disorders, various ulcers and the like.
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