688781-75-1Relevant articles and documents
Discovery of small molecule FLT3 inhibitors that are able to overcome drug-resistant mutations
Chen, Ming,Lai, Shusheng,Li, Bolin,Li, Linli,Nan, Jinshan,Shen, Chenjian,Wang, Tianqi,Wang, Yifei,Yang, Shengyong,Zhang, Guo,Zhang, Wenqing,Zhong, Jiemin
supporting information, (2020/10/02)
Herein we report the discovery of 1-(5-(tert-butyl)isoxazol-3-yl)-3- (3-fluorophenyl)urea derivatives as new FLT3 inhibitors that are able to overcome the drug resistance mutations: the secondary D835Y and F691L mutations on the basis of the internal tandem duplications (ITD) mutation of FLT3 (FLT3-ITD/D835Y and FLT3-ITD/F691L, respectively). The most potent compound corresponds to 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3- fluorophenyl)urea (4d), which showed IC50s (half maximal inhibitory concentrations) of 0.072 nM, 5.86 nM and 3.48 nM against FLT3-ITD, FLT3-ITD/F691L and FLT3-ITD/D835Y, respectively. Compound 4d also showed good selectivity for FLT3 in a kinase profiling assay. Collectively, 4d could be a good lead compound and deserves further in-depth studies.
Compound and application thereof in preparation of drugs for treating diseases caused by high expression of Flt3/c-Met kinase
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, (2020/12/29)
The invention belongs to the technical field of chemical drug synthesis, and provides a compound and application thereof in preparation of drugs for treating diseases caused by high expression of Flt3/cMet kinase. The compound provided by the invention is prepared by amidation reaction of an intermediate A and an intermediate B. The compound provided by the invention has a strong effect of inhibiting Flt3/cMet kinase. The invention also discloses application of the compound and salt, solvate or prodrug thereof, or application of a pharmaceutical composition composed of one of the compound, salt, hydrate, solvate and prodrug thereof and an excipient in preparation of drugs for treating diseases caused by abnormal high expression of Flt3/cMet kinase, and application in drugs for treating and/or preventing proliferative diseases or cancers.
Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety as potential antitumor inhibitor
Chen, Ting,Duan, Yongli,Huang, Shunmin,Liu, Huimin,Tang, Qidong,Xiong, Hehua,Zhang, Jianqing,Zheng, Pengwu
, (2019/12/25)
A series of pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety were designed, synthesized and evaluated for the anti-proliferative on three cancer cell lines (A549, HepG2 and MCF-7) in vitro. Most of the compounds showed moderate to high potency. Some excellent compounds were tested for the inhibitory activity of c-Met kinase. Compound 34 (c-Met IC50 = 17 nM) was investigated the selectivity against Flt-3, c-Kit, VEGFR-2, ALK, PDGFR-β and RON. Structure-activity relationship studies indicated that hydrogen, fluorine atom, and mono-electron-withdrawing groups (mono-EWGs, such as R2 = F) on R, R1 and R2, respectively, were beneficial for the anti-proliferative activities of the target compounds. Besides, we have took further study on the combined mode between compound 34 and c-Met kinase through molecular docking.
Synthesis and antiproliferative activity of pyrrolo[2,3-b]pyridine derivatives bearing the 1,8-naphthyridin-2-one moiety
Tang, Qidong,Duan, Yongli,Wang, Linxiao,Wang, Min,Ouyang, Yiqiang,Wang, Caolin,Mei, Han,Tang, Sheng,Xiong, Yinhua,Zheng, Pengwu,Gong, Ping,Zhu, Wufu
, p. 266 - 275 (2017/12/07)
A series of pyrrolo[2,3-b]pyridine derivatives bearing the 1,8-naphthyridin-2-one moiety were synthesized, and evaluated for their antiproliferative activity against four cancer cell lines (HT-29, A549, H460, and U87MG) and six tyrosine kinases (c-Met, Flt-3, PDGFR-β VEGFR-2, EGFR, and c-Kit) inhibitory activities in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 32 showing Flt-3/c-Met IC50 value of 1.16/1.92 nM. Structure-activity relationship studies indicated that the hydrogen atom served as R1 group was benefited to the potency, and mono-electron-withdrawing groups (mono-EWGs) on the phenyl ring (such as R3 = 4-F) showed a higher preference for antiproliferative activity.
Synthesis and bioevaluation and doking study of 1H-pyrrolo[2,3-b]pyridine derivatives bearing aromatic hydrazone moiety as c-Met inhibitors
Wang, Wenhui,Xu, Shan,Duan, Yongli,Liu, Xiaobo,Li, Xiaojing,Wang, Caolin,Zhao, Bingbing,Zheng, Pengwu,Zhu, Wufu
, p. 315 - 327 (2018/01/17)
Two series of aromatic hydrazone derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (7a–r, 8a–i, 12a–b, 13a–c, 16a–d and 17a–e) were designed, synthesized and evaluated for the IC50 values against four cancer cell lines (A549, HepG2, MCF-7and PC-3). Two selected compounds (7c and 17e) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2 and EGFR kinases. The data indicated that targets compounds were selective for c-Met kinase. And the most promising compound 7c was further studied in terms of dose-dependent, time-dependent and cell apoptosis. Most of the compounds showed excellent cytotoxicity activity, especially the most promising compound 7c with the IC50 values of 0.82 ± 0.08 μM, 1.00 ± 0.11 μM, 0.93 ± 0.28 μM and 0.92 ± 0.17 μM against A549, HepG2, MCF-7 and PC-3 cell lines and 0.506 μM against c-Met kinase. Structure–activity relationships (SARs) and docking studies indicated that the activities of the phenyl hydrazone derivatives (7a–r and 8a–i) were superior to that of the heterocyclic hydrazone series (12a–b, 13a–c, 16a–d and 17a–e). What's more, the further studies indicated that the target compounds can induce apoptosis of A549 cells and arrest efficiently the cell cycle progression in G2/M phase of A549 cells.
Discovery of novel pyrrolo-pyridine/pyrimidine derivatives bearing pyridazinone moiety as c-Met kinase inhibitors
Wang, Lin Xiao,Liu, Xiaobo,Xu, Shan,Tang, Qidong,Duan, Yongli,Xiao, Zhen,Zhi, Jia,Jiang, Liwen,Zheng, Pengwu,Zhu, Wufu
, p. 538 - 551 (2017/11/01)
In continue to our previous research, eight series of pyrrolo[2,3-b]pyridine and pyrrolo[2,3-d]pyrimidine derivatives bearing pyridazinone moiety were designed, synthesized, and the in vitro antitumor activity was evaluated against four cancer cell lines (A549, HepG2, MCF-7 and PC-3). Some selected compounds (22f, 22g, 26c and 26e) were evaluated for the activity against c-Met kinase, and according to the results of kinase inhibitory activity, the compound 22g was further evaluated for other four tyrosine kinases (Flt-3, VEGFR-2, c-Kit and EGFR) to test the enzyme-based selectivity. The most promising compound 22g showed excellent activity than lead compound Foretinib against A549, HepG2, MCF-7 and PC-3 cell lines, with the IC50 values of 2.19 ± 0.45 μM, 1.32 ± 0.26 μM, 6.27 ± 1.04 μM and 4.63 ± 0.83 μM. The structure–activity relationships (SARs) and docking studies indicated that the pyrrolo[2,3-b]pyridine derivatives bearing 4-oxo-pyridazinone moiety was superior to the pyrrolo[2,3-d]pyrimidine derivatives bearing 6-oxo-pyridazinone moiety. What's more, the target compounds modified with X and Y (X = H, Y = H) were favorable to the activity. And electron drawing groups (EWGs) of 4-Cl-3CF3 on the aryl group show the best activity.
Discovery of novel 7-azaindole derivatives bearing dihydropyridazine moiety as c-Met kinase inhibitors
Tang, Qidong,Wang, Linxiao,Duan, Yongli,Wang, Wenhui,Huang, Shunmin,Zhi, Jia,Jia, Shuang,Zhu, Wufu,Wang, Ping,Luo, Rong,Zheng, Pengwu
, p. 97 - 106 (2017/04/07)
A series of 7-azaindole derivatives bearing the dihydropyridazine scaffold were synthesized and evaluated for their c-Met kinase inhibitory, and antiproliferative activity against 4 cancer cell lines (HT29, A549, H460, U87MG) were evaluated in?vitro. Most compounds showed moderate to excellent potency. Compared to foretinib, the most promising analog 34 (c-Met IC50: 1.06?nM, a multitarget tyrosine kinase inhibitor) showed a 6.4-, 7.8-, and 3.2-fold increase in activity against HT29, A549, and H460?cell lines, respectively. Structure activity relationship studies indicated that mono-EWGs (such as R2?=?F) at 4-position of moiety D was a key factor in improving the antitumor activity.
Polysubstituted quinolone compounds, and preparation method and use thereof
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, (2017/09/19)
The invention provides polysubstituted quinolone compounds, and a preparation method and a use thereof, and concretely provides a polysubstituted quinolone compound represented by formula I, and optical isomers, pharmaceutically acceptable salts or solvates thereof. All groups in the formula I are defined in the description. The quinolone compound has excellent c-Met inhibition activity, and can be used for treating c-Met activity or expression level corrected diseases.
Design, synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors
Zhu, Wufu,Wang, Wenhui,Xu, Shan,Tang, Qidong,Luo, Rong,Wang, Min,Gong, Ping,Zheng, Pengwu
, p. 812 - 819 (2016/02/09)
Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a-e, 13a-f, 14a-f and 15a-i) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC50 values of 1.04 ± 0.11 μM, 0.02 ± 0.01 μM and 9.11 ± 0.55 μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC50 values: 0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure-activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.
Synthesis, and docking studies of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors
Zhu, Wufu,Wang, Wenhui,Xu, Shan,Wang, Jianqiang,Tang, Qidong,Wu, Chunjiang,Zhao, Yanfang,Zheng, Pengwu
, p. 1749 - 1756 (2016/04/05)
Four series of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (14a-e, 15a-g, 16a-e and 17a-g) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Four selected compounds (15e, 16a-b and 17a) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 valuables in single-digit μM to nanomole range. Eleven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC50 values of 0.14 ± 0.08 μM, 0.24 ± 0.07 μM and 0.02 ± 0.01 μM, which were 4.6, 1.6 and 473.5 times more active than Foretinib (0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure-activity relationships (SARs) and docking studies indicated that the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What's more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity.
