796967-57-2Relevant academic research and scientific papers
Discovery of novel anti-angiogenesis agents. Part 8: Diaryl thiourea bearing 1H-indazole-3-amine as multi-target RTKs inhibitors
Sun, Ying,Shan, Yuanyuan,Li, Chuansheng,Si, Ru,Pan, Xiaoyan,Wang, Binghe,Zhang, Jie
, p. 373 - 385 (2017/10/16)
VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti-proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4.
Discovery of novel anti-angiogenesis agents. Part 7: Multitarget inhibitors of VEGFR-2, TIE-2 and EphB4
Li, Chuansheng,Shan, Yuanyuan,Sun, Ying,Si, Ru,Liang, Liyuan,Pan, Xiaoyan,Wang, Binghe,Zhang, Jie
, p. 506 - 518 (2017/11/14)
Herein, we embarked on a structural optimization campaign aiming at the discovery of second generation anti-angiogenesis agents with our previously reported BPS-7 as lead compound. A library of 27 compounds has been afforded based on the highly conserved ATP-binding pocket of VEGFR-2, Tie-2, and EphB4. Several title compounds exhibited simultaneous inhibitory effects against three angiogenic RTKs. These compounds with a ‘triplet’ inhibition profile have been identified as novel anti-angiogenic and anticancer agents. The representative VDAU11 displayed prominent anti-angiogenic and anticancer potency and could be considered as a candidate for further optimization. These results indicate that N-(pyridin-2-yl)acrylamide could serve as a novel hinge-binding group of triple inhibitors.
Bis-aryl urea derivatives as potent and selective LIM kinase (Limk) inhibitors
Yin, Yan,Zheng, Ke,Eid, Nibal,Howard, Shannon,Jeong, Ji-Hak,Yi, Fei,Guo, Jia,Park, Chul Min,Bibian, Mathieu,Wu, Weilin,Hernandez, Pamela,Park, Hajeung,Wu, Yuntao,Luo, Jun-Li,Lograsso, Philip V.,Feng, Yangbo
, p. 1846 - 1861 (2015/04/21)
The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 400-fold), potent inhibition of cofilin phosphorylation in A7r5, PC-3, and CEM-SS T cells (IC50 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 μM inhibited only Limk1 and STK16 with ≥80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.
INDAZOLE INHIBITORS OF KINASE
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Page/Page column 19, (2011/11/30)
The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, wherein A1, A2, A3 and L are defined in the description. The present invention relates also to methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as aurora and KDR.
Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N′-(2-fluoro-5- methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor
Dai, Yujia,Hartandi, Kresna,Ji, Zhiqin,Ahmed, Asma A.,Albert, Daniel H.,Bauch, Joy L.,Bouska, Jennifer J.,Bousquet, Peter F.,Cunha, George A.,Glaser, Keith B.,Harris, Christopher M.,Hickman, Dean,Guo, Jun,Li, Junling,Marcotte, Patrick A.,Marsh, Kennan C.,Moskey, Maria D.,Martin, Ruth L.,Olson, Amanda M.,Osterling, Donald J.,Pease, Lori J.,Soni, Niru B.,Stewart, Kent D.,Stoll, Vincent S.,Tapang, Paul,Reuter, David R.,Davidsen, Steven K.,Michaelides, Michael R.
, p. 1584 - 1597 (2008/02/01)
In our continued efforts to search for potent and novel receptor tyrosine kinase (RTK) inhibitors as potential anticancer agents, we discovered, through a structure-based design, that 3-aminoindazole could serve as an efficient hinge-binding template for kinase inhibitors. By incorporating an N,N′-diaryl urea moiety at the C4-position of 3-aminodazole, a series of RTK inhibitors were generated, which potently inhibited the tyrosine kinase activity of the vascular endothelial growth factor receptor and the platelet-derived growth factor receptor families. A number of compounds with potent oral activity were identified by utilizing an estradiol-induced mouse uterine edema model and an HT1080 human fibrosarcoma xenograft tumor model. In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models.
Thienopyridine urea inhibitors of KDR kinase
Heyman, H. Robin,Frey, Robin R.,Bousquet, Peter F.,Cunha, George A.,Moskey, Maria D.,Ahmed, Asma A.,Soni, Niru B.,Marcotte, Patrick A.,Pease, Lori J.,Glaser, Keith B.,Yates, Melinda,Bouska, Jennifer J.,Albert, Daniel H.,Black-Schaefer, Candace L.,Dandliker, Peter J.,Stewart, Kent D.,Rafferty, Paul,Davidsen, Steven K.,Michaelides, Michael R.,Curtin, Michael L.
, p. 1246 - 1249 (2007/10/03)
A series of substituted thienopyridine ureas was prepared and evaluated for enzymatic and cellular inhibition of KDR kinase activity. Several of these analogs, such as 2, are potent inhibitors of KDR (10 nM) in both enzymatic and cellular assays. Further
