- Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold
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Both histone deacetylase (HDAC) and fibroblast growth factor receptor (FGFR) are important targets for cancer therapy. Although combining dual HDAC pharmacophore with tyrosine kinase inhibitors (TKIs) had achieved a successful progress, dual HDAC/FGFR1 inhibitors haven't been reported yet. Herein, we designed a series of hybrids bearing 1H-indazol-3-amine and benzohydroxamic acids scaffold with scaffold hopping and molecular hybridization strategies. Among them, compound 7j showed the most potent inhibitory activity against HDAC6 with IC50 of 34 nM and exhibited the great inhibitory activities against a human breast cancer cell line MCF-7 with IC50 of 9 μM in vitro. Meanwhile, the compound also exhibited moderate FGFR1 inhibitory activities. This study provides new tool compounds for further exploration of dual HDAC/FGFR1 inhibition.
- Liu, Jian,Qian, Chengbo,Zhu, Yehua,Cai, Jianguo,He, Yufang,Li, Jie,Wang, Tianlin,Zhu, Haohao,Li, Zhi,Li, Wei,Hu, Lihong
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Read Online
- Design, synthesis and biological evaluation of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol-1-yl)acetamide derivatives as potent VEGFR-2 inhibitors
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Vascular endothelial growth factor-2 (VEGFR-2) plays a pivotal role in tumor angiogenesis. Herein, a library of novel 2-(4-(1H-indazol-6-yl)-1H-pyrazol -1-yl)acetamide derivatives were designed and synthesized as VEGFR-2 inhibitors based on scaffold hopping strategy. These compounds exhibited the excellent inhibitory in both VEGFR-2 and tumor cells proliferation. Especially, compound W13 possessed potent VEGFR-2 inhibition with IC50 = 1.6 nM and anti-proliferation against HGC-27 tumor cells with IC50 = 0.36 ± 0.11 μM, as well as less toxicity against normal GES-1 cells with IC50 = 187.46 ± 10.13 μM. Moreover, W13 obviously inhibited colony formation, migration and invasion of HGC-27 cells by adjusting the expression of MMP-9 and E-cadherin, and induced HGC-27 cells apoptosis by increasing ROS production and regulating the expression of apoptotic proteins. Furthermore, W13 blocked the PI3K-Akt-mTOR signaling pathway in HGC-27 cells. In addition, anti-angiogenesis of W13 was proved by inhibiting tube formation and the expression of p-VEGFR-2 in HUVEC cells. All the results demonstrated that W13 could be developing as a promising anticancer agent for gastric cancer therapy.
- Wang, Xing-Rong,Wang, Shuai,Li, Wen-Bo,Xu, Kai-Yan,Qiao, Xue-Peng,Jing, Xue-Li,Wang, Zi-Xiao,Yang, Chang-jiang,Chen, Shi-Wu
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- Synthesis and SAR studies of 3,6-disubstituted indazole derivatives as potent hepcidin production inhibitors
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Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of indazole compounds as hepcidin production inhibitors. The optimization study of compound 1 led to a potent hepcidin production inhibitor 45, which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.
- Fukuda, Takeshi,Ueda, Kenjiro,Ishiyama, Takashi,Goto, Riki,Muramatsu, Sumie,Hashimoto, Masami,Watanabe, Kengo,Tanaka, Naoki
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- Design, synthesis, and biological evaluation of indazole derivatives as selective and potent FGFR4 inhibitors for the treatment of FGF19-driven hepatocellular cancer
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Fibroblast growth factor receptor 4 (FGFR4) is a member of the fibroblast growth factor receptor family, which is closely related to the occurrence and development of hepatocellular carcinoma (HCC). In this article, a series of indazole derivatives were designed and synthesized by using computer-aided drug design (CADD) and structure-based design strategies, and then they were evaluated for their inhibition of FGFR4 kinase and antitumor activity. F-30 was subtly selective for FGFR4 compared to FGFR1; it affected cell growth and migration by inhibiting FGFR4 pathways in HCC cell lines in a dose-dependent manner.
- Chen, Xiaolu,Liu, Yanan,Zhang, Liting,Chen, Daoxing,Dong, Zhaojun,Zhao, Chengguang,Liu, Zhiguo,Xia, Qinqin,Wu, Jianzhang,Chen, Yongheng,Zheng, Xiaohui,Cai, Yuepiao
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Read Online
- From Fragment to Lead: De Novo Design and Development toward a Selective FGFR2 Inhibitor
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Fibroblast growth factor receptors (FGFRs) are implicated in a range of cancers with several pan-kinase and selective-FGFR inhibitors currently being evaluated in clinical trials. Pan-FGFR inhibitors often cause toxic side effects and few examples of subtype-selective inhibitors exist. Herein, we describe a structure-guided approach toward the development of a selective FGFR2 inhibitor. De novo design was carried out on an existing fragment series to yield compounds predicted to improve potency against the FGFRs. Subsequent iterative rounds of synthesis and biological evaluation led to an inhibitor with nanomolar potency that exhibited moderate selectivity for FGFR2 over FGFR1/3. Subtle changes to the lead inhibitor resulted in a complete loss of selectivity for FGFR2. X-ray crystallographic studies revealed inhibitor-specific morphological differences in the P-loop which were posited to be fundamental to the selectivity of these compounds. Additional docking studies have predicted an FGFR2-selective H-bond which could be utilized to design more selective FGFR2 inhibitors.
- Burns, Julie E.,Fishwick, Colin W. G.,Hubball, Ryan A.,Knowles, Margaret A.,Lin, Chi-Chuan,Orritt, Kyle M.,Trinh, Chi H.,Turner, Lewis D.
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- BENZO- AND PYRIDO-PYRAZOLES AS PROTEIN KINASE INHIBITORS
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The invention relates to new chemical compounds of Formula (I), pharmaceutical compositions containing them, and their use for the pharmacological treatment of a cancer, preferably a glioblastoma.
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Page/Page column 48
(2020/10/28)
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- Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening
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Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0 nM) and modest anti-proliferative activity (IC50 = 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3 nM) and cellular activity (IC50 = 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.
- Liu, Jian,Wen, Yu,Gao, Lina,Gao, Liang,He, Fengjun,Zhou, Jingxian,Wang, Junwei,Dai, Rupeng,Chen, Xiaojing,Kang, Di,Hu, Lihong
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- PYRIDONE DERIVATIVES AND THEIR USE AS KINASE INHIBITORS
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Disclosed in the present application is a compound of formula (I) as defined herein as well as a pharmaceutical composition comprising said compound. Further disclosed in the present application is the use of such pharmaceutical compositions for treating diseases, namely inter alia for use in the treatment of cancer, metabolic, inflammatory, autoimmune and viral diseases. The compounds disclosed herein are inhibitors of MNK1 and/or MNK2 kinases.
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Page/Page column 195; 196
(2017/05/10)
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- Discovery of DS79182026: A potent orally active hepcidin production inhibitor
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Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of benzisoxazole compounds as orally active hepcidin production inhibitors. The optimization study of multi kinase inhibitor 1 led to a potent and bioavailable hepcidin production inhibitor 38 (DS79182026), which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.
- Fukuda, Takeshi,Goto, Riki,Kiho, Toshihiro,Ueda, Kenjiro,Muramatsu, Sumie,Hashimoto, Masami,Aki, Anri,Watanabe, Kengo,Tanaka, Naoki
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supporting information
p. 3716 - 3722
(2017/07/27)
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- Discovery of DS28120313 as a potent orally active hepcidin production inhibitor: Design and optimization of novel 4,6-disubstituted indazole derivatives
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Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD). Here, we report the design, synthesis and structure–activity relationships (SAR) of a series of 4,6-disubstituted indazole compounds as hepcidin production inhibitors. The optimization study of multi-kinase inhibitor 1 led to the design of a potent and bioavailable hepcidin production inhibitor, 32 (DS28120313), which showed serum hepcidin-lowering effects in an interleukin-6-induced acute inflammatory mouse model.
- Fukuda, Takeshi,Goto, Riki,Kiho, Toshihiro,Ueda, Kenjiro,Muramatsu, Sumie,Hashimoto, Masami,Aki, Anri,Watanabe, Kengo,Tanaka, Naoki
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supporting information
p. 5252 - 5257
(2017/10/30)
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- Optimization of 1H-indazol-3-amine derivatives as potent fibroblast growth factor receptor inhibitors
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Fibroblast growth factor receptor (FGFR) is a potential target for cancer therapy because of its critical role in promoting cancer formation and progression. In a continuing effort to improve the cellular activity of hit compound 7r bearing an indazole scaffold, which was previously discovered by our group, several compounds harnessing fluorine substituents were designed, synthesized and biological evaluated. Besides, the region extended out to the ATP binding pocket toward solvent was also explored. Among them, compound 2a containing 2,6-difluoro-3-methoxyphenyl residue exhibited the most potent activities (FGFR1: less than 4.1?nM, FGFR2: 2.0?±?0.8?nM). More importantly, compound 2a showed an improved antiproliferative effect against KG1 cell lines and SNU16 cell lines with IC50 values of 25.3?±?4.6?nM and 77.4?±?6.2?nM respectively.
- Cui, Jing,Peng, Xia,Gao, Dingding,Dai, Yang,Ai, Jing,Li, Yingxia
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supporting information
p. 3782 - 3786
(2017/07/27)
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- Indazoles compound and its preparation and use (by machine translation)
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This invention belongs to the field of medicine synthesis, relates to novel indazoles, preparation method and application thereof, and containing said compounds as pharmaceutical composition of the active ingredient, and for preparing same as a medicament for the treatment of diseases related to tyrosine kinase FGFR, in particular of the FGFR associated the use of the medicament of cancer. Indazoles of this invention shown in a chemical formula represented by the following formula I, wherein the substituents are as defined in the specification; the compound by biological experimental results show that, for the fibroblast growth factor receptor (FGFR) has good inhibitory activity, can be used as a preparation for prevention and treatment of diseases associated with FGFR pharmaceutical, in particular for preparing and treating of FGFR-related cancer. (by machine translation)
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Paragraph 0047; 0048; 0049
(2017/02/02)
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- SILYL-CONTAINING HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to novel Silyl-Containing Heterocyclic Compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, B, C, D, E, F and L are as defined herein. The present invention also relates to compositions comprising at least one Silyl-Containing Heterocyclic Compound, and methods of using the Silyl-Containing Heterocyclic Compounds for treating or preventing HCV infection in a patient.
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Page/Page column 107-108
(2013/03/28)
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- HEPATITIS C VIRUS INHIBITORS
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This disclosure concerns novel compounds of Formula (I) as defined in the specification and compositions comprising such novel compounds. These compounds are useful antiviral agents, especially in inhibiting the function of the NS5A protein encoded by Hepatitis C virus (HCV). Thus, the disclosure also concerns a method of treating HCV related diseases or conditions by use of these novel compounds or a composition comprising such novel compounds.
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Page/Page column 64
(2010/12/26)
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