- Discovery of Potent, Selective Triazolothiadiazole-Containing c-Met Inhibitors
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Herein, we report a novel series of highly potent and selective triazolothiadiazole c-Met inhibitors. Starting with molecule 5, we have applied structure-based drug design principles to identify the triazolothiadiazole ring system. We successfully replaced the metabolically unstable phenolic moiety with a quinoline group. Further optimization around the 5,6 bicyclic moiety led to the identification of 21. Compound 21 suffered from PDE3 selectivity issues and subsequent, structurally informed design led to the discovery of compound 23. Compound 23 has exquisite kinase selectivity, excellent potency, favorable ADME profile, and showed dose-dependent antitumor efficacy in a SNU-5 gastric cancer xenograft model.
- Aronov, Alex M.,Boucher, Diane,Deininger, David D.,Ford, Pamella J.,Giroux, Simon,Lauffer, David J.,Li, Pan,Liang, Jianglin,McGinty, Kira,Moody, Cameron S.,Ronkin, Steven,Swett, Rebecca,Tang, Qing,Waal, Nathan
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supporting information
p. 955 - 960
(2021/06/25)
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- FUNCTIONALISED AND SUBSTITUTED INDOLES AS ANTI-CANCER AGENTS
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The present invention relates to anti-tropomyosin compounds, processes for their preparation, and methods for treating or preventing a disease or disorder, such as a proliferative disease (preferably cancer), using compounds of the invention.
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Page/Page column 67
(2016/02/05)
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- COMPOUNDS AND METHODS
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The present invention relates to novel retinoid-related orphan receptor gamma (RORγ) modulators and their use in the treatment of diseases mediated by RORy.
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- Lessons from (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3- b ]pyridazin-3-yl)ethyl)quinoline (PF-04254644), an inhibitor of receptor tyrosine kinase c-met with high protein kinase selectivity but broad phosphodiesterase family inhibition lea
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The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many cancers and plays important roles in tumor invasive growth and metastasis. An exclusively selective c-Met inhibitor (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)- [1,2,4]triazolo[4,3-
- Cui, J. Jean,Shen, Hong,Tran-Dubé, Michelle,Nambu, Mitchell,McTigue, Michele,Grodsky, Neil,Ryan, Kevin,Yamazaki, Shinji,Aguirre, Shirley,Parker, Max,Li, Qiuhua,Zou, Helen,Christensen, James
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p. 6651 - 6665
(2013/10/01)
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- A TRIAZOLOTHIADIAZOLE INHIBITOR OF C-MET PROTEIN KINASE
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The present invention relates to compound (1), which is useful in the inhibition of c-Met protein kinase. The invention also provides pharmaceutically acceptable compositions comprising Compound (1) and methods of using the compositions in the treatment of proliferative disorders.
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Page/Page column 20-21
(2010/07/10)
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- HETEROCYCLIC KINASE MODULATORS
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The present disclosure provides heterocyclic protein kinase modulators and methods of using these compounds to treat diseases mediated by kinase activity.
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Page/Page column 110; 115
(2009/01/20)
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- TRIAZOLOPYRIDAZINE DERIVATIVES
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The invention relates to compounds of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 and R3' are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula (I) and to methods of treating hyperproliferative disorders in a mammal by administering the compounds of formula (I).
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Page/Page column 28-29
(2008/06/13)
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