1394166-10-9Relevant academic research and scientific papers
Discovery of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline moiety as promising antitumor drug candidate
Chen, Tao,Fang, Wei-Rong,Huang, Wei,Li, Yun-Man,Liu, Peng-Fei,Zhuo, Lin-Sheng
, (2020/02/29)
A series of 1,6-naphthyridinone-based MET kinase inhibitors bearing quinoline moiety in block A were designed and synthesized based on the structures of Cabozantinib and our reported compound IV. Extensive SAR and DMPK studies led to the identification of 20j, a potent and orally bioavailable MET kinase inhibitor with favorable kinase selectivity. More importantly, 20j exhibited statistically significant tumor growth inhibition (Tumor growth inhibition/TGI of 131%, 4/6 partial regression/PR) in the U-87 MG xeograft model, which is superior to that of Cabozantinib (TGI of 97%, 2/6 PR), and significantly better than that of compound IV (TGI of 15%, 0/6 PR) at the same dose (12.5 mg/kg). Combined with favorable in vitro potency, kinase selectivity, pharmacokinetic profile and in vivo efficacy, the promising antitumor drug candidate 20j has subsequently advanced into preclinical research.
Design, synthesis and evaluation of sulfonylurea-containing 4-phenoxyquinolines as highly selective c-Met kinase inhibitors
Nan, Xiang,Jiang, Yi-Fan,Li, Hui-Jing,Wang, Jun-Hu,Wu, Yan-Chao
, p. 2801 - 2812 (2019/05/15)
Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of 4-phenoxyquinoline derivatives bearing sulfonylurea moiety were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against tested four cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant potency as compared with foretinib, with the most promising compound 13x (c-Met kinase IC50 = 1.98 nM) demonstrated relatively good selectivity versus 10 other tyrosine kinases and remarkable cytotoxicities against HT460, MKN-45, HT-29 and MDA-MB-231 with IC50 values of 0.055 μM, 0.064 μM, 0.16 μM and 0.49 μM, respectively. The preliminary structure activity relationships indicated that a sulfonylurea moiety as linker as well as mono-EGWs (such as R1 = 4-F) on the terminal phenyl rings contributed to the antitumor activity.
Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities
Qi, Baohui,Yang, Ying,He, Huan,Yue, Xupeng,Zhou, Yuting,Zhou, Xing,Chen, Yuying,Liu, Min,Zhang, Anmian,Wei, Fachang
, p. 368 - 380 (2018/02/14)
A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging.
Quinoxalinone-containing 4-phenoxy substituted quinoline compound and application thereof
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, (2018/10/11)
The invention relates to quinoxalinone-containing 4-phenoxy substituted quinoline derivatives shown as a general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein the substituent groups Ar, R1, R2 and n have meanings as shown in the description. The invention further relates to a compound with the general formula I having a strong effect of inhibitingc-Met kinase, and further relates to application of the compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparation of medicines for treating and/or preventing diseases caused by abnormal high expression of the c-Met kinase, particularly application in preparation of medicines for treating and/or preventing cancers.
4-phenoxyl substituted quinoline compound containing 2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one and imidazole and application of compound
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, (2018/01/09)
The invention relates to a quinoline derivative shown as the general formula I and containing 2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one and imidazole, and pharmaceutically acceptable salt, hydrate, solvate or prodrug of the quinoline derivative. In the general formula I, Ar, R1, R2, L, and n have meanings as the description defined. The invention further relates to a great c-Met kinase inhibiting effect of the compound shown as the general formula I, and applications of pharmaceutically acceptable salt, hydrate, solvate or prodrug of the compound to prepare medicines for treating and/or preventing diseases caused by abnormal high expression of c-Met kinase, particularly an application of preparing a medicine for treating and/or preventing cancer.
Dihydropyridazinone containing quinoline compound and use thereof
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, (2016/10/10)
The invention relates to a dihydropyridazinone containing quinoline derivative shown as general formula I and its pharmaceutically acceptable salt, solvate or prodrug. Specifically, the substituents AR, R1, R2, R3, X, Y and n have the meaning given in the specification. The invention also relates to the strong c-Met kinase inhibition effect of the compound shown as the general formula I, and also relates to use of the compound and its pharmaceutically acceptable salt, solvate or prodrug in preparation of drugs treating and/or preventing diseases caused by c-Met kinase abnormal high expression, especially the use in preparation of drugs treating and/or preventing cancers. (formula I).
Containing 1, 2, 3-triazole quinoline compound and its preparation method and application
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, (2016/10/20)
The invention relates to a quinoline derivative containing 1,2,3-triazole of the formula I as shown in the specification, and a pharmaceutically acceptable salt, solvate or prodrug of the quinoline derivative, and in the formula I, substituent groups Ar, R1, R2, R3, X, Y and n are defined as shown in the specification. The invention further relates to a compound of the formula I, and the compound has a relatively high function of inhibiting c-Met tyrosine kinase. Furthermore, the invention further relates to an application of the compound as well as a pharmaceutically acceptable salt, solvate or prodrug of the compound in preparing a medicine for treating and/or preventing diseases caused by abnormal high-expression c-Met tyrosine kinase, and particularly an application in preparing a medicine for treating and/or preventing cancer.
Discovery of a novel 6,7-disubstituted-4-(2-fluorophenoxy)quinolines bearing 1,2,3-triazole-4-carboxamide moiety as potent c-Met kinase inhibitors
Liu, Mingmei,Hou, Yunlei,Yin, Weile,Zhou, Shunguang,Qian, Ping,Guo, Zhuang,Xu, Liying,Zhao, Yangfang
, p. 96 - 108 (2016/05/24)
A series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety were designed, synthesized and evaluated for their in vitro cytotoxic activities against four typical cancer cell lines (A549, H460, HT-29, and MKN-45). Most compounds showed moderate-to-excellent antiproliferative activity. Compounds 32, 36, 37, 45, 51, and 52 were further examined for their inhibitory activity against c-Met kinase. The promising compound 37, with a c-Met IC50 value of 2.27 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. The analysis of their structure-activity relationships indicated that compounds with EWGs, especially chloro group, at 2-position on the phenyl ring (moiety B) have potent antitumor activity.
Design, synthesis and biological evaluation of novel 4-phenoxy-6,7-disubstituted quinolines possessing (thio)semicarbazones as c-Met kinase inhibitors
Zhai, Xin,Bao, Guanglong,Wang, Limei,Cheng, Mingke,Zhao, Meng,Zhao, Sijia,Zhou, Hongyang,Gong, Ping
, p. 1331 - 1345 (2016/03/01)
In continuing our efforts to identify small molecules able to inhibit c-Met kinase, three series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives (23a-w, 26a-d and 30a-d) bearing (thio)semicarbazone scaffold were designed, synthesized and evaluated for their cytotoxicity. The biological data revealed that most compounds exhibited moderate-to-excellent activity against HT-29, MKN-45, A549 cancer cell lines and relative poor potency toward MDA-MB-231 cell as well as hardly any cytotoxicity in normal PBL cell. Eleven compounds were further examined for their inhibitory activity against c-Met kinase and three compounds (23h, 23n and 26a) demonstrated good inhibitory activity. This work resulted in the discovery of a potent c-Met inhibitor 23n, bearing 2-hydroxy-3-allylphenyl group at R2 moiety, as a valuable lead molecule, which possessed remarkable cytotoxicity and high selectivity against A549 and HT-29 cell lines with IC50 values of 11 nM and 27 nM. Besides, it displayed excellent c-Met kinase inhibition on a single-digital nanomolar level (IC50 = 1.54 nM). Meanwhile, the results from preliminarily in vivo study reflected that compound 23n showed promising overall PK profiles, consistent with the efficacy in both MKN-45 and HT-29 tumor xenograft mice model. These results clearly indicated that compound 23n is a potent and highly selective c-Met inhibitor and its favorable in vitro and in vivo profiles warrant further investigation.
Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors
Liu, Ju,Nie, Minhua,Wang, Yanjing,Hu, Jinxing,Zhang, Feng,Gao, Yanlin,Liu, Yajing,Gong, Ping
, p. 431 - 446 (2016/08/04)
A series of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety were synthesized and evaluated for their in?vitro cytotoxic activity against four cancer cell lines (HT-29, H460, A549 and MKN-45). Most of the compounds exhibited moderate-to-significant cytotoxicity. Compounds 33, 37, 39, 44, 46, 47, 53, 55, 61, 64 and 66 were further examined for their inhibitory activity against c-Met kinase. The most promising compound 47 (with c-Met IC50value of 1.57?nM) showed remarkable cytotoxicity against HT-29, H460, A549 and MKN-45?cell lines with IC50values of 0.08?μM, 0.14?μM, 0.11?μM and 0.031?μM, respectively, and thus it was 1.1- to 2.3- fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.
