- Design and synthesis of newer N-benzimidazol-2yl benzamide analogues as allosteric activators of human glucokinase
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Allosteric activators of human glucokinase (GK) had revealed significant hypoglycemic effects for therapy of type-2 diabetes (T2D) in animal as well as human models. Some newer N-benzimidazol-2yl substituted benzamide analogues were prepared and assessed for activation of GK accompanied by molecular docking investigations for predicting the bonding interactions of these derivatives with the residues in allosteric site of GK protein. Amongst the derivatives synthesized, compounds 2 and 7 strongly increased catalytic action of GK (GK activation fold >2.0 in comparison to control) in vitro. The results of in-vitro testing were supported by the molecular docking investigations of these analogues with GK protein’s allosteric site residues (showed appreciable H-bond interactions with Arg63 residue of GK). Derivatives investigated in present study afforded few lead compounds for the discovery of harmless and strong allosteric GK activating compounds for treating T2D.
- Singh, Sukhbir,Arora, Sandeep,Dhalio, Ervon,Sharma, Neelam,Arora, Kunal,Grewal, Ajmer Singh
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p. 760 - 770
(2021/01/20)
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- PYRIDINE COMPOUND SUBSTITUTED WITH AZOLE
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The present invention provides a compound represented by formula [I] shown below or a pharmaceutically acceptable salt thereof that has an inhibitory effect on 20-HETE producing enzyme. (in formula [I] above, the structure represented by formula [II] below: represents any of the structures represented by formula group [III] below: R1, R2, R3, and R4 independently represent a hydrogen atom, a fluorine atom, methyl, or the like, R5 represents any of the structures represented by formula group [IV]:
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Paragraph 0943
(2020/07/07)
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- BACE-2 INHIBITORY COMPOUNDS AND RELATED METHODS OF USE
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Provided herein are novel compounds of Formulae I-III, and methods of using the same to selectively inhibit BACE2.
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Paragraph 0140; 0144; 0157; 0158
(2017/05/02)
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- COMPOUNDS, IN PARTICULAR FOR USE IN THE TREATMENT OF A DISEASE OR CONDITION FOR WHICH A BROMODOMAIN INHIBITOR IS INDICATED
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The invention relates to a compound for use in the treatment of a disease or condition for which a bromodomain inhibitor is indicated characterized by a general formula (1) and a compound according to formula (3).
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Page/Page column 50
(2016/01/25)
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- Synthesis and biological evaluation of novel (E)-N′-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides as potent LSD1 inhibitors
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Lysine specific demethylase 1 (LSD1) plays an important role in regulating histone lysine methylation at residues K4 and K9 on histone H3 and is recognized as an attractive therapeutic target in multiple malignancies. In this study, a series of novel (E)-N′-(2,3-dihydro-1H-inden-1-ylidene) benzohydrazides were synthesized and biologically evaluated for their potential LSD1 inhibitory effect. Among them, compounds 5a and 5n showed the most potent LSD1 inhibitory activity with IC50values of 1.4 and 1.7?nM, respectively, which were about 10 times more potent compared with (E)-N-(1-(5-chloro-2-hydroxyphenyl) ethylidene)-3-(morpholinosulf-only) benzohydrazide (J. Med. Chem. 2013, 56, 9496–9508; as reference compound). Compounds 5a and 5n also exhibited marked anti-proliferation activities against cancer cell lines that highly expressed LSD1. These results suggest that these optimized compounds might be served as promising LSD1 inhibitors against cancer, which merit further study.
- Zhou, Yang,Li, Yan,Wang, Wen-Jing,Xiang, Pu,Luo, Xin-Mei,Yang, Li,Yang, Sheng-Yong,Zhao, Ying-Lan
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p. 4552 - 4557
(2016/08/24)
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- N'-Alkylaminosulfonyl Analogues of 6-Fluorobenzylideneindolinones with Desirable Physicochemical Profiles and Potent Growth Inhibitory Activities on Hepatocellular Carcinoma
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The benzylideneindolinone 6-chloro-3-(3′-trifluoromethylbenzylidene)-1,3-dihydroindol-2-one (4) was reported to exhibit potent and selective growth inhibitory effects on hepatocellular carcinoma (HCC). Corroborative evidence supported multi-receptor tyrosine kinase (RTK) inhibition as a possible mode of action. However, the poor physicochemical properties of 4 limited its furtherance as a lead compound. In this study, the modification of 4 was investigated with the aim of improving its potency and physicochemical profile. The 6-fluorobenzylideneindolinone 3-12 bearing a 3′-N-propylaminosulfonyl substituent was found to be a promising substitute. Compound 3-12 [6-fluoro-3-(3′-N-propylaminosulfonylbenzylidene)-1,3-dihydroindol-2-one] was found to be tenfold more soluble than 4 and to have sub-micromolar growth inhibitory activities on HCC cells. It is apoptogenic and inhibits the phosphorylation of several RTKs in HuH7, of which the inhibition of FGFR4 and HER3 are prominent. Compound 3-12 decreased the tumor load in a physiologically relevant orthotopic HCC xenograft murine model. Structure-activity relationships support pivotal roles for the fluoro and N′-propylaminosulfonyl moieties in enhancing cell-based activity and moderating the physicochemical profile (solubility, permeability) of 3-12.
- Chen, Xiao,Yang, Tianming,Deivasigamani, Amudha,Shanmugam, Muthu K.,Hui, Kam-Man,Sethi, Gautam,Go, Mei-Lin
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supporting information
p. 1548 - 1558
(2015/09/07)
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- BENZYLIDENE-INDOLINONE COMPOUNDS AND THEIR MEDICAL USE
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Compounds of general formula I: wherein R1a, R1b, R2, R3a, R3b and X are as defined herein are tyrosine kinase inhibitors and are useful for the treatment of various diseases and conditions, for examp
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Paragraph 0233; 0236-0237
(2013/03/26)
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- NOVEL QUINOLINE ESTERS USEFUL FOR TREATING SKIN DISORDERS
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Disclosed are quinoline esters of Formula (I): which are useful as Liver X receptors (LXR) modulators. Pharmaceutical compositions containing quinoline esters of Formula (I) and the use of quinoline esters of Formula (I) in the safe treatment of various s
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Page/Page column 16
(2012/01/15)
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- NOVEL 1,2,4 OXADIAZOLE COMPOUNDS AND METHODS OF USE THEREOF
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The invention relates to 1,2,4 oxadiazole compounds and analogs thereof, represented by formula (II), and compositions and methods of use thereof.
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Page/Page column 63
(2009/12/28)
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- PHARMACEUTICAL COMPOSITIONS AND THEIR METHODS OF USE
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The invention relates to a composition comprising a neuronal nicotinic receptor ligand and an α4β2 positive allosteric modulator, a method of using the same, and a related article of manufacture.
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Page/Page column 56
(2008/12/06)
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- SOLUBLE DIAZOALKANE PRECURSORS
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The present invention relates to compounds useful in the preparation of diazoalkanes in general (such as diazomethane, diazoethane, diazopropane, diazobutane and homologues) and to diazomethane (CH2=N=N) in particular. The compounds chosen as the diazomethane source according to the invention also have the advantage of being water soluble. They are capable of being decomposed to diazomethane or another diazoalkane (which is allowed to bubble out of the vessel to another vessel containing a solution of reactant) and are converted to by-products that are also water-soluble.
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Page/Page column 12-13
(2008/06/13)
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- SUBSTITUTED PYRAZOLE COMPOUNDS USEFUL AS SOLUBLE EPOXIDE HYDROLASE INHIBITORS
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Disclosed are compounds active against soluble epoxide hydrolase (sEH), compositions thereof and methods of using and making same.
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Page/Page column 139
(2008/06/13)
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- ACYLATED PIPERIDIHES AS GLYCINE TRANSPORTER INHIBITORS
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The invention provides a compound of formula (I) or a salt or solvate thereof: wherein R1, n, X, Y and Z are as defined in the specification, and uses of such compounds. The compounds inhibit GlyT1 transporters and are useful in the treatment of certain neurological and neuropsychiatric disorders, including schizophrenia.
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Page/Page column 47
(2010/11/23)
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- PHENETHANOLAMINE DERIVATIVES
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The present invention relates to novel compounds of formula (I), or a salt, solvate, or physiologically functional derivative thereof, to a process for their manufacture, to pharmaceutical compositions containing them, and to their use in therapy, in particular their use in the prophylaxis and treatment of respiratory diseases.
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Page/Page column 66
(2010/02/07)
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