19335-11-6Relevant articles and documents
Design, synthesis and biological evaluation of indazole-pyrimidine based derivatives as anticancer agents with anti-angiogenic and antiproliferative activities
Elsayed, Nevine M. Y.,Abou El Ella, Dalal A.,Serya, Rabah A. T.,Tolba, Mai F.,Shalaby, Raed,Abouzid, Khaled A. M.
, p. 881 - 899 (2016)
Three series of novel indazole-pyrimidine based compounds were designed, synthesized and biologically evaluated as VEGFR-2 kinase inhibitors. The most active compound 6i (IC50 = 24.5 nM) was further evaluated against a HUVEC cell line showing an IC50 of 1.37 μM. Moreover, it showed an indirect anti-angiogenic effect through the suppression of secretion of VEGF and TGF-b1 from prostate cancer cells. Five compounds were selected by the NCI for evaluation of their in vitro anticancer activity against the full NCI panel of cell lines at 10 μM. Compounds 6e and 6f were further selected for 5-dose testing. Compound 6e exerted nanomolar GI50 values against several cell lines: CCRF-CEM (901 nM), MOLT-4 (525 nM) and CAKI-1 (992 nM) and one digit micromolar activity against the rest of the cell lines ranging from 1.05 μM to 2.41 μM. Compound 6f showed one digit micromolar activity against the whole panel of cell lines ranging from 1.55 μM to 7.4 μM. A molecular docking study was employed to investigate the predicted binding mode of the target compounds with VEGFR-2, using Autodock software. Furthermore, MD simulation was implemented for compounds 6i and 10c for further validation and rationalization of their binding mode.
Design, synthesis, and biological evaluation of new B-RafV600E kinase inhibitors
Wang, Peng-Fei,Zhang, Yong-Jiao,Wang, Dong,Hu, Hui-Min,Wang, Zhong-Chang,Xu, Chen,Qiu, Han-Yue,Zhu, Hai-Liang
, p. 2372 - 2380 (2018)
The association of deregulated signal pathways with various diseases has long been a research hotspot. One of the most important signal pathways, the MAPK (mitogen-activated protein kinase) signal pathway, plays a vital role in transducing extracellular signals into vital intracellular mechanisms. While mutations on its key component Raf kinase lead to sever diseases, targeted inhibition has thereby become an attractive therapeutic strategy. Several drugs have been approved for the treatment of Raf relevant diseases, yet more candidates are ever needed as the known drugs have confronted resistance and side effects. In the present study, we primarily investigated the binding modes of type I/II and type II inhibitors with B-Raf kinase. Based on the current knowledge, these ligands were fragmented and recombined to provide new interesting insights. Afterwards, a series of derivatives has been synthesized after the validation of hit compound. In addition, in vitro assays were carried out to profile the pharmacological properties of all the entities. Of all the compounds, compound 5h showed the best profile and may be used in the future study.
COMPOUND SERVING AS IRAK INHIBITOR
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Paragraph 0199-0200, (2021/10/07)
The present disclosure relates a compound as an IRAK inhibitor. Specifically, the present disclosure provides a compound of formula I, or a cis-trans isomer, an optical isomer, a racemate, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative thereof, a hydrate or a solvate thereof. The compounds disclosed herein have potent inhibitory effects on IRAK and thus have therapeutic effect on IRAK-related diseases.
Discovery of 1-(1H-indazol-4-yl)-3-((1-phenyl-1H-pyrazol-5-yl)methyl) ureas as potent and thermoneutral TRPV1 antagonists
Kang, Jin Mi,Kwon, Sun Ok,Ann, Jihyae,Blumberg, Peter M.,Ha, Heejin,Yoo, Young Dong,Frank-Foltyn, Robert,Lesch, Bernhard,Bahrenberg, Gregor,Stockhausen, Hannelore,Christoph, Thomas,Lee, Jeewoo
, (2020/10/06)
A series of 1-indazol-3-(1-phenylpyrazol-5-yl)methyl ureas were investigated as hTRPV1 antagonists. The structure–activity relationship study was conducted systematically for both the indazole A-region and the 3-trifluoromethyl/t-butyl pyrazole C-region to optimize the antagonism toward the activation by capsaicin. Among them, the antagonists 26, 50 and 51 displayed highly potent antagonism with Ki(CAP) = 0.4–0.5 nM. Further, in vivo studies in mice indicated that these derivatives both antagonized capsaicin induced hypothermia, consistent with their in vitro activity, and themselves did not induce hyperthermia. In the formalin model, 51 showed anti-nociceptive activity in a dose-dependent manner.
