- PPARs-FXR multi-target micromolecular agonist as well as preparation method and application thereof
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The invention discloses a PPARs-FXR multi-target micromolecule agonist and a preparation method and application thereof, the structure is shown in a general formula I, and the definition of each substituent group is shown in the description and claims. Th
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Paragraph 0092; 0095; 0097; 0125-0129
(2021/05/22)
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- COMPOUNDS FOR MODULATING FXR
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Provided herein are compounds of Formula (I), a stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof; wherein variables are as defined herein; and their pharmaceutical compositions, which are useful as modulators of the activity of Farnesoid X receptors (FXR).
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Paragraph 000140; 000152; 000153; 00519; 000521; 000522
(2020/12/30)
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- Highly Modular Flow Cell for Electroorganic Synthesis
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A highly modular electrochemical flow cell and its application in electroorganic synthesis is reported. This innovative setup facilitates many aspects: an easy adjustment of electrode distance, quick exchange of electrode material, and the possibility to easily switch between a divided or undivided cell. However, the major benefit of the cell is the exact thermal positioning of the electrode material into a Teflon piece. Thereby, the application of expensive and nonmachinable electrode materials like boron-doped diamond or glassy carbon can easily be realized in flow cells. By this geometry, the maximum surface of such valuable electrode materials is exploited. The cell size can compete with classical preparative approaches in terms of performance and productivity. The optimization of reaction parameters and an easy up-scaling to larger flow cells is possible. By using this cell, the starting material can be saved in the development of the electroorganic transformations. To demonstrate the utility of this particular cell, two transformations of important building blocks for the fine chemical and pharmaceutical industry were established including an efficient and simple workup protocol.
- Gütz, Christoph,Stenglein, Andreas,Waldvogel, Siegfried R.
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p. 771 - 778
(2017/05/29)
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- Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism
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Farnesoid X receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4′-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50=12.2±0.2μM). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR. X marks the spot: 39 trisubstituted isoxazoles were designed and synthesized, leading to compounds with pharmacological profiles ranging from agonist to antagonist at the farnesoid X receptor (FXR). By using the most potent antagonist as a probe, the essential molecular basis of FXR antagonism is proposed, and E467 on H12 can be regarded as a hot-spot residue for the future design of nonsteroidal antagonists of FXR.
- Huang, Huang,Si, Pei,Wang, Lei,Xu, Yong,Xu, Xin,Zhu, Jin,Jiang, Hualiang,Li, Weihua,Chen, Lili,Li, Jian
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p. 1184 - 1199
(2015/07/07)
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- Design, Synthesis, and in Vitro Evaluation of Novel 3, 7-Disubstituted Coumarin Derivatives as Potent Anticancer Agents
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Twenty-seven 3, 7-disubstituted coumarin derivatives were designed, synthesized, and evaluated in vitro as anticancer agents. Most of the compounds showed moderate-to-potent antiproliferative activity against K562 cells. Compounds 7b and 7d were chosen to evaluate the concentration of 50% growth inhibition (GI50) against SN12C, OVCAR, BxPC-3, KATO-III, T24, SNU-1, WiDr, HeLa, K562, and AGS cell lines. The most potent compound 7d was selected for further cell cycle arrest assay in the AGS cell line. The in vitro data indicated that methylation of benzimidazole moiety at the 3-position of coumarin exhibited significant enhancement of anticancer activity. This study should provide important information for further modification and optimization of coumarin derivatives as anticancer agents.
- Wang, Yubin,Liu, Haitao,Lu, Peng,Mao, Rui,Xue, Xiaojian,Fan, Chen,She, Jinxiong
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p. 637 - 647
(2015/03/14)
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- Synthesis of 1,2,3-triazole substituted isoxazoles via copper (I) catalyzed cycloaddition
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The synthesis of a series of 3,5-disubstituted isoxazole-4-carboxylic esters containing N-substituted 1,2,3-triazoles (V) starting from various benzaldehydes (I) is reported. Benzaldehydes undergo oximation with hydroxylamine hydrosulfate. Later, chlorination followed by condensation with methylacetoacetate and the hydrolysis of the resulting ester afforded respective carboxylic acid (II), which on chlorination with PCl5 gave the corresponding acid chlorides (III). The coraboxylic acid chlorides (III) on propargylation gave propargylic esters (IV) and these on click reaction gave the title compounds (V).
- Ramana, P. Venkata,Reddy, A. Ram
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p. 621 - 627
(2012/09/07)
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- IL17 AND IFN-GAMMA INHIBITION FOR THE TREATMENT OF AUTOIMMUNE INFLAMMATION
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The present invention relates to compounds of the general formula (I), and the pharmaceutically acceptable salt or solvate thereof, as anti-inflammatory and immunomodulatory agents.
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Page/Page column 14
(2012/08/08)
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- IL17 AND IFN-GAMMA INHIBITION FOR THE TREATMENT OF AUTOIMMUNE INFLAMMATION
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The present invention relates to compounds of the general formula (I), and the pharmaceutically acceptable salt or solvate thereof, as anti-inflammatory and immunomodulatory agents.
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Page/Page column 29
(2012/08/08)
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- Electrochemical and yeast-catalysed ring-opening of isoxazoles in the synthesis of analogues of the herbicide Grasp
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Isoxazoles substituted with an electron-withdrawing group at the 4-position undergo electrochemical and yeast-catalysed N-O bond cleavage. The electrolysis is much more efficient and, with acyl- and alkoxycarbonyl-substituted isoxazoles, it affords the enolised dicarbonylimine functionality characteristic of the herbicide Grasp. Regioisomeric 4- and 5-substituted isoxazoles are accessible through nitrile oxide cycloaddition chemistry, using halogen as a steric auxiliary to control the regiochemistry of reaction. Crystal data for compounds 11 and 19b are presented.
- Easton,Heath,Hughes,Lee,Savage,Simpson,Tiekink,Vuckovic,Webster
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p. 1168 - 1174
(2007/10/03)
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