- Malononitrile: A versatile d1-synthon for the synthesis of hetero-aromatic carboxylic acid derivatives
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A convenient one-pot synthesis of heteroaromatic carboxylic acid derivatives from malononitrile substituted heteroaromatic compounds, namely pyridines, pyrimidines, and 1,3,5-triazines is described. In this procedure, the oxidation of malononitriles with
- Brünjes, Marco,Ford, Mark James,Dietrich, Hansj?rg,Wilson, Kirsty
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- Furanone derivatives, preparation method and use thereof
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The invention relates to a novel selective cyclooxygenase-2 inhibitor compound, a preparation method and use and belongs to the field of chemical drugs. The compound represented by a formula (I) shown in the description can be used for inhibiting cyclooxy
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Paragraph 0165; 0166; 0169; 0170
(2019/05/04)
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- Structural basis and SAR for G007-LK, a lead stage 1,2,4-triazole based specific tankyrase 1/2 inhibitor
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Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological biotargets with possible applications for the development of novel anticancer therapeutics. A focused structure-activity relationship study was conducted based on the tankyrase inhibitor JW74 (1). Chemical analoging of 1 improved the 1,2,4-triazole based core and led to 4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5- (methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triazol-3-yl}ethenyl]-1,3, 4-oxadiazol-2-yl}benzonitrile (G007-LK), a potent, "rule of 5" compliant and a metabolically stable TNKS1/2 inhibitor. G007-LK (66) displayed high selectivity toward tankyrases 1 and 2 with biochemical IC50 values of 46 nM and 25 nM, respectively, and a cellular IC50 value of 50 nM combined with an excellent pharmacokinetic profile in mice. The PARP domain of TNKS2 was cocrystallized with 66, and the X-ray structure was determined at 2.8 ? resolution in the space group P3221. The structure revealed that 66 binds to unique structural features in the extended adenosine binding pocket which forms the structural basis for the compound's high target selectivity and specificity. Our study provides a significantly optimized compound for targeting TNKS1/2 in vitro and in vivo.
- Voronkov, Andrew,Holsworth, Daniel D.,Waaler, Jo,Wilson, Steven R.,Ekblad, Bie,Perdreau-Dahl, Harmonie,Dinh, Huyen,Drewes, Gerard,Hopf, Carsten,Morth, Jens P.,Krauss, Stefan
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p. 3012 - 3023
(2013/06/04)
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- TRIAZOLE DERIVATIVES AS WNT SIGNALING PATHWAY INHIBITORS
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The present invention relates to compounds of formula (I), to processes for their preparation, to pharmaceutical formulations containing such compounds and to their use in therapy: Such compounds find particular use in the treatment and/or prevention of conditions or diseases which are affected by over-activation of signaling in the Wnt pathway and increased presence of nuclear β-catenin. For example, these may be used in preventing and/or retarding proliferation of tumor cells and metastasis, for example carcinomas such as colon carcinomas.
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