- Discovery of 2-substituted-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide as potent and selective protein arginine methyltransferases 5 inhibitors: Design, synthesis and biological evaluation
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Protein arginine methyltransferases 5 (PRMT5) represents an attractive drug target in epigenetic field for the treatment of leukemia and lymphoma. Here, a series of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amide derivatives targeting PRMT5 were designed with structure-based approach and synthesized. Among them, compound 46 showed potent and selective PRMT5 inhibition activity with an IC50 of 8.5 nM, which was approximately equivalent with the phase I clinical trial PRMT5 inhibitor GSK-3326595 (IC50 = 5.5 nM). Compound 46 also displayed pronounced anti-proliferative activity in MV4-11 cells (GI50 = 18 nM) and antitumor activity in MV4-11 mouse xenografts model. This molecule can serve as an excellent tool compound for probing the biological function of PRMT5.
- Shao, Jingwei,Zhu, Kongkai,Du, Daohai,Zhang, Yuanyuan,Tao, Hongrui,Chen, Zhifeng,Jiang, Hualiang,Chen, Kaixian,Luo, Cheng,Duan, Wenhu
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p. 317 - 333
(2019/01/04)
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- Azacyclic derivative as well as preparation method and medical use thereof
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The invention relates to an azacyclic derivative as well as a preparation method and medical use thereof and particularly relates to an azacyclic derivative represented by a general formula (I) (shownin the description), a preparation method thereof, a pharmaceutical composition containing the derivative and use of the derivative as an SMO antagonist, particularly in the treatment of diseases such as cancer related to Hedgehog signal channels. The definitions of groups in the general formula (I) are same as the definitions in the description.
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Paragraph 0376; 0377; 0378; 0379; 0380
(2019/02/04)
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- Preparation method of 1-aminoisoquinoline-6-methanol
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The invention relates to a synthesis method of 1-aminoisoquinoline-6-methanol. The synthesis method comprises the following steps: reacting 6-bromoisoquinoline used as a raw material to form 6-cyanoisoquinoline; adding a sulfuric acid solution to obtain isoquinoline-6-carboxylic acid; further obtaining isoquinoline-6-methyl formate under the action of absolute methanol and thionyl chloride; further adding m-chloroperoxybenzoic acid in batches in dichloromethane, and reacting to obtain a mixture isoquinoline-6-methyl formate oxynitride; adding into phosphorus oxychloride in batches, cooling after the reaction is completed, pouring into cracked ice, and precipitating a solid 1-chloroisoquinoline-6-methyl formate crude product; directly extracting the water phase with ethyl acetate, and performing centrifugal drying to obtain another 1-chloroisoquinoline-6-methyl formate crude product; merging the crude products of two batches, passing through a silica gel column, and eluting to obtain 1-chloroisoquinoline-6-methyl formate; adding into tetrahydrofuran, then cooling to -30 DEG C, and adding lithium aluminum hydride in batches to obtain a 1-(1-chloroisoquinoline-6-yl)methanol product; mixing with p-methoxybenzylamine, and heating to obtain (1-(4-methoxybenzylamino)isoquinoline-6-yl)methanol; and adding into trifluoroacetic acid, and refluxing to obtain the final product 1-aminoisoquinoline-6-methanol. The method is reasonable in route, low in waste, high in yield and easy to operate, and realizes raw material saving.
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Paragraph 0020; 0023
(2017/08/29)
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- Design, synthesis, and evaluation of novel porcupine inhibitors featuring a fused 3-ring system based on the ‘reversed’ amide scaffold
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The Wnt signaling pathway is an essential signal transduction pathway which leads to the regulation of cellular processes such as proliferation, differentiation and migration. Aberrant Wnt signaling is known to have an association with multiple cancers. Porcupine is an enzyme that catalyses the addition of palmitoleate to a serine residue in Wnt proteins, a process which is required for the secretion of Wnt proteins. Here we report the synthesis and structure–activity-relationship of the novel porcupine inhibitors based on a ‘reversed’ amide scaffold. The leading compound 53 was as potent as the clinical compound LGK974 in a cell based STF reporter gene assay. Compound 53 potently inhibited the secretion of Wnt3A, therefore was confirmed to be a porcupine inhibitor. Furthermore, compound 53 showed excellent chemical and plasma stabilities. However, the clearance of compound 53 in liver microsomal tests was moderate to high, and the solubility of compound 53 was suboptimal. Collective efforts toward further optimization of this novel tricyclic template to develop better porcupine inhibitors will be subsequently undertaken and reported in due course.
- Xu, Zhixiang,Xu, Xiangxiang,O'Laoi, Ruadhan,Ma, Haikuo,Zheng, Jiyue,Chen, Shuaishuai,Luo, Lusong,Hu, Zhilin,He, Sudan,Li, Jiajun,Zhang, Hongjian,Zhang, Xiaohu
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p. 5861 - 5872
(2016/10/30)
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- NOVEL DIHYDROPYRIMIDIN-2(1H)-ONE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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The present invention is directed to novel dihydropyrimidin-2(1H)-one compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 157
(2011/04/24)
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- Azole-based inhibitors of AKT/PKB for the treatment of cancer
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Through a combination of screening and structure-based rational design, we have discovered a series of N1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma.
- Zeng, Qingping,Allen, John G.,Bourbeau, Matthew P.,Wang, Xianghong,Yao, Guomin,Tadesse, Seifu,Rider, James T.,Yuan, Chester C.,Hong, Fang-Tsao,Lee, Matthew R.,Zhang, Shiwen,Lofgren, Julie A.,Freeman, Daniel J.,Yang, Suijin,Li, Chun,Tominey, Elizabeth,Huang, Xin,Hoffman, Douglas,Yamane, Harvey K.,Fotsch, Christopher,Dominguez, Celia,Hungate, Randall,Zhang, Xiaoling
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scheme or table
p. 1559 - 1564
(2010/06/16)
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- HETEROCYCLIC MODULATORS OF PKB
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The invention relates to heterocyclic compounds of Formula I and compositions thereof useful for treating diseases mediated by protein kinase B (PKB) where the variables have the definitions provided herein Formula (I). The invention also relates to the therapeutic use of such compounds and compositions thereof in treating disease states associated with abnormal cell growth, cancer, inflammation, and metabolic disorders.
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Page/Page column 97
(2009/03/07)
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- NOVEL ANTIMALARIA AGENT CONTAINING HETEROCYCLIC COMPOUND
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Disclosed is an antimalarial agent containing a compound represented by the formula: [wherein A1 represents a 3-pyridyl group that may have a substituent, a 6-quinolyl group that may have a substituent, or the like; X1 represents a group represented by the formula -C(=O)-NH- or the like; E represents a furyl group, a thienyl group or a phenyl group; with the proviso that A1 may have one to three substituents, and E has one of two substituents] or a salt thereof or hydrates thereof.
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Page/Page column 58
(2008/06/13)
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- NOVEL ANTIFUNGAL AGENT COMPRISING HETEROCYCLIC COMPOUND
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The present invention provides an antifungal agent represented by the formula: [wherein A1 represents a 3-pyridyl group which may have a substituent, a quinolyl group which may have a substituent, or the like; X1 represents a group represented by the formula -NH-C(=O)-, a group represented by the formula -C(=O)-NH-, or the like; E represents a furyl group, a thienyl group, a pyrrolyl group, a phenyl group, a pyridyl group, a tetrazolyl group, a thiazolyl group or a pyrazolyl group; with the proviso that A1 may have 1 to 3 substituents, and E has one or two substituents].
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Page/Page column 66
(2010/11/08)
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