179873-51-9Relevant articles and documents
Potent Inhibition of Nicotinamide N-Methyltransferase by Alkene-Linked Bisubstrate Mimics Bearing Electron Deficient Aromatics
Buijs, Ned,Campagna, Roberto,Emanuelli, Monica,Gao, Yongzhi,Innocenti, Paolo,Jespers, Willem,Martin, Nathaniel I.,Parsons, Richard B.,Sartini, Davide,Van Haren, Matthijs J.,Van Westen, Gerard J. P.,Zhang, Yurui,Gutiérrez-De-Terán, Hugo
, p. 12938 - 12963 (2021/09/11)
Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3) to generate 1-methylnicotinamide (MNA). NNMT overexpression has been linked to a variety of diseases, most prominently human cancers, indicating its potential as a therapeutic target. The development of small-molecule NNMT inhibitors has gained interest in recent years, with the most potent inhibitors sharing structural features based on elements of the nicotinamide substrate and the S-adenosyl-l-methionine (SAM) cofactor. We here report the development of new bisubstrate inhibitors that include electron-deficient aromatic groups to mimic the nicotinamide moiety. In addition, a trans-alkene linker was found to be optimal for connecting the substrate and cofactor mimics in these inhibitors. The most potent NNMT inhibitor identified exhibits an IC50 value of 3.7 nM, placing it among the most active NNMT inhibitors reported to date. Complementary analytical techniques, modeling studies, and cell-based assays provide insights into the binding mode, affinity, and selectivity of these inhibitors.
Quinoline compounds and preparation method thereof, and intermediate, pharmaceutical composition and application of quinoline compounds
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Paragraph 0440-0442, (2018/02/04)
The invention discloses quinoline compounds and a preparation method thereof, and an intermediate, a pharmaceutical composition and application of quinoline compounds. The invention provides quinoline compounds disclosed as Formula 1, and pharmaceutically acceptable salts, solvates, metabolites, metabolism precursors or pharmaceutical precursors thereof. The quinoline compounds have favorable inhibitory effects on tyrosine kinase C-Met, and can be used for preparing drugs for prevention, treatment or auxiliary treatment on multiple diseases related to C-Met expression or activity, and especially neoplastic diseases.
Synthesis and biological evaluation of 4(5)-(6-methylpyridin-2-yl)imidazoles and -pyrazoles as transforming growth factor-β type 1 receptor kinase inhibitors
Kim, Dae-Kee,Lee, Yeon-Im,Lee, Yeon Woo,Dewang, Purushottam M.,Sheen, Yhun Yhong,Kim, Yeo Woon,Park, Hyun-Ju,Yoo, Jakyung,Lee, Ho Soon,Kim, Yong-Kook
scheme or table, p. 4459 - 4467 (2010/08/22)
A series of 4(5)-(6-methylpyridin-2-yl)imidazoles 16-19 and -pyrazoles 22-29, 33, and 34 have been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in cell-based luciferase reporter assays. The 6-quinolinyl imidazole analogs 16 and 18 inhibited ALK5 phosphorylation with IC50 values of 0.026 and 0.034 μM, respectively. In a luciferase reporter assay using HaCaT cells transiently transfected with p3TP-luc reporter construct, 18 displayed 66% inhibition at 0.05 μM, while competitor compounds 2 and 3 showed 44% inhibition. The binding mode of 18 generated by flexible docking studies with ALK5:18 complex shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions.
