- COMPOUNDS AND METHODS FOR MODULATING SPLICING
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The present disclosure features compounds and related compositions that, inter alia, modulate nucleic acid splicing, e.g., splicing of a pre-mRNA, as well as methods of use thereof.
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Page/Page column 205-206
(2021/09/04)
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- TRIAZOLOBENZAZEPINES AS VASOPRESSIN V1A RECEPTOR ANTAGONISTS
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The present invention relates to 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine derivatives of general formula (I) and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof which are centrally and/or peripherally acting V1a receptor modulators, particularly V1a receptor antagonists. Additional subject of the present invention is the process for the preparation of the compounds and the intermediates of the preparation process as well. The invention also relates to the pharmaceutical compositions containing the compounds or together with one or more other active substances, as well as to the use in the treatment and/or prophylaxis of a disease or condition associated with V1a receptor function.
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Page/Page column 101; 107
(2019/07/19)
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- Dual inhibitors of RAF-MEK-ERK and PI3K-PDK1-AKT pathways: Design, synthesis and preliminary anticancer activity studies of 3-substituted-5-(phenylamino) indolone derivatives
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The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I–III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III) > 3-alkenyl-5-(phenylamino) indolone (Series I) > 3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC50 value of 1.8 ± 0.8 μM in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.
- Yu, Zutao,Chen, Zhuo,Su, Qiongli,Ye, Shiqi,Yuan, Hongbo,Kuai, Mengni,Lv, Meng,Tu, Zhijun,Yang, Xiaoping,Liu, RangRu,Hu, Gaoyun,Li, Qianbin
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supporting information
p. 944 - 954
(2019/02/20)
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- Disubstituted indol-2(1H)-one derivative and preparation method and application thereof
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The invention discloses a disubstituted indol-2(1H)-one derivative and a preparation method and application thereof. The chemical structural formula of the disubstituted indol-2(1H)-one derivative is shown in the description. The derivative can be applied to preparation of antitumor medicine.
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Paragraph 0064; 0065
(2017/05/27)
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- Tricyclic oxazolidone comound, and preparation method and use thereof
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The invention relates to a novel tricyclic oxazolidone comound, and a preparation method and a use thereof, and concretely discloses a compound with the structure represented by formula I, an enantiomer, a diastereomer or a raceme thereof or a mixture of the enantiomer, the diastereomer and the raceme, or a pharmaceutically acceptable salt thereof. The formula I is shown in the specification. The invention also discloses a preparation method of the compound, and an application of the compound in FXa target related disease treatment drugs.
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Paragraph [0449]
(2016/10/07)
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- Design, synthesis, and structure-activity and structure-pharmacokinetic relationship studies of novel [6,6,5] tricyclic fused oxazolidinones leading to the discovery of a potent, selective, and orally bioavailable FXa inhibitor
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The blood coagulation enzyme factor Xa (FXa) is a particularly promising target for anticoagulant therapy, and identification of oral small-molecule inhibitors of FXa remains a research focus. On the basis of the X-ray crystal structure of FXa and its inhibitor rivaroxaban, we designed and synthesized a series of conformationally restricted mimics containing a novel [6,6,5] tricyclic fused oxazolidinone scaffold. Intensive structure-activity relationship (SAR) and structure-pharmacokinetic relationship (SPR) studies on this new series led to the discovery of compound 11a: a highly potent, selective, direct, and orally bioavailable FXa inhibitor with excellent in vivo antithrombotic efficacy and preferable pharmacokinetic profiles. Druggability evaluation of compound 11a was undertaken and elicited positive outcomes. All results indicate that compound 11a is a promising drug candidate for the prevention and treatment of thromboembolic diseases in venous and arterial systems.
- Xue, Tao,Ding, Shi,Guo, Bin,Zhou, Yuren,Sun, Peng,Wang, Heyao,Chu, Wenjing,Gong, Guoqing,Wang, Yinye,Chen, Xiaoyan,Yang, Yushe
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supporting information
p. 7770 - 7791
(2014/12/11)
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- SUBSTITUTED PYRROLE-2, 5-DIONES AS PROTEIN KINASE C INHIBITORS
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A compound of formula (I) wherein R, Ra and Rb are as defined in the specification, processes for their production, their uses, in particular in transplantation, and pharmaceutical compositions containing them.
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Page/Page column 4
(2008/06/13)
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