56137-52-1Relevant articles and documents
Preparation method and application of compound containing zinc-bound and quinoline skeleton
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Paragraph 0139-0140; 0143-0144, (2021/11/10)
The invention relates to the field of pharmaceutical chemistry, in particular to a novel zinc-containing binding group-containing quinoline compound. A geometric isomer, a pharmaceutically acceptable salt, solvate or prodrug thereof, a preparation method and thereof, and a pharmaceutical composition containing the compound. The invention also relates to an application of the compound in preparation of drugs for treating and/or preventing diseases mediated by c-Met tyrosine kinase and HDAC. The quinoline compounds, geometric isomers and pharmaceutically acceptable salts, solvates and prodrugs thereof are shown in the specification, and R. 1 , m, Q, X, As described in the claims and the description.
Discovery and Structure-Based Optimization of Next-Generation Reversible Methionine Aminopeptidase-2 (MetAP-2) Inhibitors
Heinrich, Timo,Seenisamy, Jeyaprakashnarayanan,Blume, Beatrix,Bomke, J?rg,Calderini, Michel,Eckert, Uwe,Friese-Hamim, Manja,Kohl, Rainer,Lehmann, Martin,Leuthner, Birgitta,Musil, Djordje,Rohdich, Felix,Zenke, Frank T.
, p. 5025 - 5039 (2019/05/22)
Co- and post-translational processing are crucial maturation steps to generate functional proteins. MetAP-2 plays an important role in this process, and inhibition of its proteolytic activity has been shown to be important for angiogenesis and tumor growth, suggesting that small-molecule inhibitors of MetAP-2 may be promising options for the treatment of cancer. This work describes the discovery and structure-based hit optimization of a novel MetAP-2 inhibitory scaffold. Of critical importance, a cyclic tartronic diamide coordinates the MetAP-2 metal ion in the active site while additional side chains of the molecule were designed to occupy the lipophilic methionine side chain recognition pocket as well as the shallow cavity at the opening of the active site. The racemic screening hit from HTS campaign 11a was discovered with an enzymatic IC50 of 150 nM. The resynthesized eutomer confirmed this activity and inhibited HUVEC proliferation with an IC50 of 1.9 μM. Its structural analysis revealed a sophisticated interaction pattern of polar and lipophilic contacts that were used to improve cellular potency to an IC50 of 15 nM. In parallel, the molecular properties were optimized on plasma exposure and antitumor efficacy which led to the identification of advanced lead 21.
Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives
Norman, Mark H.,Liu, Longbin,Lee, Matthew,Xi, Ning,Fellows, Ingrid,D'Angelo, Noel D.,Dominguez, Celia,Rex, Karen,Bellon, Steven F.,Kim, Tae-Seong,Dussault, Isabelle
scheme or table, p. 1858 - 1867 (2012/05/05)
Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as MET gene amplification in human cancers, points to c-Met as a
