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.
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.
IMIDAZO [1,2-B] PYRIDAZINE DERIVATIVES FOR THE TREATMENT OF C-MET TYROSINE KINASE MEDIATED DISEASE
-
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).
