- TGF-betaR1 inhibitor and application thereof
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The invention belongs to the field of medical chemistry, and particularly relates to a compound serving as a TGF-betaR1 inhibitor and application of the compound. Specifically, the invention providesa compound shown as a formula I or an isomer, a pharmaceutically acceptable salt, a solvate, a crystal or a prodrug thereof, a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds or the composition to treatment and/or prevention of TGF-betaR1 related diseases, such as cancers, tissue hyperplasia diseases, fibrosis and inflammatory diseases. The compound provided by the invention shows significant inhibitory activity on TGF-betaR1 kinase, and is very expected to become a therapeutic agent for TGF-betaR1 related diseases.
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Paragraph 0806; 0811-0813
(2020/06/09)
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- Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-β type 1 receptor inhibitors
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Inhibition of transforming growth factor β (TGF-β) type 1 receptor (ALK5) provides a feasible approach for the treatment of fibrotic diseases and malignant tumors. In this study, we designed and synthesized a new series of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives, and evaluated biologically as TGF-β type 1 receptor inhibitors. The most potent compound 15r inhibited the ALK5 enzyme and NIH3T3 cell viability with IC50 values of 44 and 42.5 nM, respectively. Compound 15r also displayed better oral plasma exposure and excellent bioavailability than LY-3200882, and in vivo inhibited 65.7% of the tumor growth in a CT26 xenograft mouse model.
- Chang, Shaohua,Guo, Zhuang,Li, Xue,Sun, Tianwen,Wang, Hai,Wang, Xiaowei,Wang, Yazhou,Xu, Guofeng,Xu, Tianwei,Yu, Wenying,Yu, Zhuangzhuang,Zhang, Yan,Zhao, Liwen
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supporting information
(2020/05/08)
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- Multigram Synthesis of C 4/C5 3,3-Difluorocyclobutyl-Substituted Building Blocks
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An approach for the multigram synthesis of 3,3-difluorocyclobutyl-substituted building blocks (including carboxylic acid, amines, alcohols, azide, trifluoroborate ketone) is described. It is shown that, in most cases, ethyl 3,3-difluorocyclobutanecarboxylate is a convenient common synthetic intermediate to obtain the target derivatives. For preparation of 3,3-difluorocyclobutanol or -cyclobutanone, an alternative pathway via reaction of dichloroketene and tert -butyl or benzyl vinyl ether should be applied.
- Melnykov, Kostiantyn P.,Granat, Dmitriy S.,Volochnyuk, Dmitriy M.,Ryabukhin, Sergey V.,Grygorenko, Oleksandr O.
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p. 4949 - 4957
(2018/12/13)
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