253801-04-6Relevant articles and documents
Synthesis and evaluation of the epithelial-to- mesenchymal inhibitory activity of indazole-derived imidazoles as dual ALK5/p38α MAP inhibitors
Liu, Yue Ying,Guo, Zhen,Wang, Jing Ying,Wang, Hui Min,Da Qi, Jun,Ma, Juan,Piao, Hu-Ri,Jin, Cheng Hua,Jin, Xuejun
, (2021)
Drugs of targeting both activin receptor-like kinase 5 (ALK5) and p38α have therapeutic advantages, making them attractive treatment options for tumors. Two series of 4-(1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazoles 13a–g and 4-(1-methyl-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazoles 20a–g were synthesized and evaluated for ALK5 and p38α mitogen-activated protein kinase inhibitory activity. The most potent compound, 13c (J-1090), inhibited ALK5- and p38α-mediated phosphorylation with half-maximal inhibitor concentrations of 0.004 μM and 0.004 μM, respectively, in the enzymatic assay. In this study, the effectiveness of 13c in transforming growth factor (TGF-β)-exposed U87MG cells was investigated using western blotting, immunofluorescence assays, cell migration assay, invasion assay, and RT-PCR analysis. 13c inhibited the protein expression of Slug and the protein and RNA expression of the mesenchymal-related proteins N-cadherin and vimentin. Furthermore, 13c markedly suppressed TGF-β-induced epithelial-to-mesenchymal transition (EMT), migration, and invasion in U87MG cells. These results suggest that 13c is a novel inhibitor of ALK5 with potential utility in the treatment of human glioma.
Imidazole derivative containing indazole structure as well as preparation method and application thereof
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Page/Page column 21, (2021/01/28)
The invention relates to an imidazole derivative containing an indazole structure as well as a preparation method and application of the imidazole derivative, and belongs to the technical field of medicine synthesis. The imidazole derivative disclosed by the invention is an imidazole compound containing an indazole structure as shown in a structural formula (I) and pharmaceutically acceptable saltor hydrate thereof. The imidazole derivative containing the indazole structure has inhibitory activity on transforming growth factor beta1 receptor kinase (ALK5), can inhibit a TGF -beta induced EMT-like process, has a potential anti-cancer effect on malignant glioma, and can be used for treating human glioma related to an epithelial-mesenchymal transition (EMT)-like process.
Carboxamides vs. methanimines: Crystal structures, binding interactions, photophysical studies, and biological evaluation of (indazole-5-yl)methanimines as monoamine oxidase B and acetylcholinesterase inhibitors
Tzvetkov, Nikolay T.,Stammler, Hans-Georg,Georgieva, Maya G.,Russo, Daniela,Faraone, Immacolata,Balacheva, Aneliya A.,Hristova, Silvia,Atanasov, Atanas G.,Milella, Luigi,Antonov, Liudmil,Gastreich, Marcus
, p. 404 - 422 (2019/07/03)
A comprehensive study was performed for the first time to compare two structurally related substance classes, namely indazole-5-carboxamides (11–16) and (indazole-5-yl)methanimines (17–22). Both chemical entities are potent, selective and reversible MAO-B inhibitors and, therefore, may serve as promising lead structures for the development of drug candidates against Parkinson's disease (PD) and other neurological disorders. Compounds 15 (Ki = 170 pM, SI = 25907) and 17 (Ki = 270 pM, SI = 16340) were the most potent and selective MAO-B inhibitors in both series. To investigate the multi-target inhibitory activity, all compounds were further screened for their potency against human AChE and BuChE enzymes. Compound 15 was found to be the most potent and selective AChE inhibitor in all series (hAChE IC50 = 78.3 ± 1.7 μM). Moreover, compounds 11 and 17 showed no risk of drug-induced hepatotoxicity and a wider safety window, as determined in preliminary cytotoxicity screening. Molecular modeling studies into the human MAO-B enzyme-binding site supported by a HYDE analysis suggested that the imine linker similarly contributes to the total binding energy in methanimines 17–22 as the amide spacer in their carboxamide analogs 11–16. Amplified photophysical evaluation of compounds 17 and 20, including single X-ray analysis, photochemical experiments, and quantum-chemical calculations, provided insights into their more favourable isomeric forms and structural features, which contribute to their biologically active form and promising drug-like properties.
Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists
Sheppeck II, James E.,Gilmore, John L.,Xiao, Hai-Yun,Dhar, T.G. Murali,Nirschl, David,Doweyko, Arthur M.,Sack, Jack S.,Corbett, Martin J.,Malley, Mary F.,Gougoutas, Jack Z.,McKay, Lorraine,Cunningham, Mark D.,Habte, Sium F.,Dodd, John H.,Nadler, Steven G.,Somerville, John E.,Barrish, Joel C.
, p. 5442 - 5447 (2013/09/23)
Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.
IMIDAZO [1,2-B] PYRIDAZINE DERIVATIVES FOR THE TREATMENT OF C-MET TYROSINE KINASE MEDIATED DISEASE
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Page/Page column 122, (2009/10/21)
The invention relates to compounds of formula (I) and salts thereof, formula (I) wherein the substituents are as defined in the specification, the application of a compound of formula (I) in a process for the treatment of the human or animal body, in particular with regard to C-Met tyrosine kinase mediated disease; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharamaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner; processes for the preparation of a compound of formula (I).
NOVEL CURCUMIN DERIVATIVE
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Page/Page column 66, (2009/12/07)
The present invention provides a novel compound that is structurally similar to curcumin and has a suppressive effect on Aβ aggregation, a degradative effect on Aβ aggregates, an inhibitory effect on β-secretase, and a protective effect on neurons. The novel compound is a compound represented by the following general formula (Ia) or a salt thereof: wherein R1 represents a 4-hydroxy-3-methoxyphenyl group or the like, and R2 represents a 1H-indol-6-yl group or the like.
4-(1H-Indazol-5-yl)-6-phenylpyrimidin-2(1H)-one analogs as potent CDC7 inhibitors
Shafer, Cynthia M.,Lindvall, Mika,Bellamacina, Cornelia,Gesner, Thomas G.,Yabannavar, Asha,Jia, Weiping,Lin, Song,Walter, Annette
supporting information; experimental part, p. 4482 - 4485 (2009/04/06)
A series of 4-(4-hydroxyphenyl)-6-phenylpyrimidin-2(1H)-ones were identified by HTS as inhibitors of CDC7. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus on removing potential metabolic liabilities and improving cellular potency.
5-HETEROARYL SUBSTITUTED INDAZOLES AS KINASE INHIBITORS
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Page/Page column 67, (2009/01/24)
The present invention relates to compounds of formula (I) or pharmaceutical acceptable salts, wherein A, R1, R2, R3 and m, 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 Glycogen Synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus Kinases (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.
MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-κB ACTIVITY AND USE THEREOF
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Page/Page column 103, (2008/12/05)
Novel non-steroidal compounds are provided which are useful in treating diseases associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-κB activity including inflammatory and immune diseases, obesity and diabetes having the structure of formula (I), its enantiomers, diastereomers, or a pharmaceutically acceptable salt, or hydrate, thereof, wherein X is (Ia); or X is (Ib); or X is (Ic); (Id) is heterocycle or heteroaryl; E is -N-, -NR1-, -O-, -S-, -SO2- or -CR2-; F is -N-, -NR1a-, -O-, -S-, SO2- or -CR2a-; G is N, -NR1b-, -O-, -S-, SO2- or -CR2b-, provided that the E-F-G containing heterocyclic ring formed does not contain a S-S or S-O bond, and at least one of E, F and G is a heteroatom; J, Ja, M, Ma, Q, Rx, Ry, R1, R1a, R1b, R2, R2a, R2b, and R3 to R21, Z, Za, Zb, and Zc are as defined above.
