- Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase
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G9a-like protein (GLP) and G9a are highly homologous protein lysine methyltransferases (PKMTs) sharing approximately 80% sequence identity in their catalytic domains. GLP and G9a form a heterodimer complex and catalyze mono- and dimethylation of histone H3 lysine 9 and nonhistone substrates. Although they are closely related, GLP and G9a possess distinct physiological and pathophysiological functions. Thus, GLP or G9a selective small-molecule inhibitors are useful tools to dissect their distinct biological functions. We previously reported potent and selective G9a/GLP dual inhibitors including UNC0638 and UNC0642. Here we report the discovery of potent and selective GLP inhibitors including 4 (MS0124) and 18 (MS012), which are >30-fold and 140-fold selective for GLP over G9a and other methyltransferases, respectively. The cocrystal structures of GLP and G9a in the complex with either 4 or 18 displayed virtually identical binding modes and interactions, highlighting the challenges in structure-based design of selective inhibitors for either enzyme.
- Xiong, Yan,Li, Fengling,Babault, Nicolas,Dong, Aiping,Zeng, Hong,Wu, Hong,Chen, Xin,Arrowsmith, Cheryl H.,Brown, Peter J.,Liu, Jing,Vedadi, Masoud,Jin, Jian
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p. 1876 - 1891
(2017/03/17)
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- IMPROVED PROCESS FOR THE PREPARATION OF APREMILAST
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The present invention relates to an improved process for the preparation of Apremilast of formula (I).
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- New synthesis process for 3-methoxyl-4-ethoxybenzonitrile
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The invention discloses a new synthesis process for 3-methoxyl-4-ethoxybenzonitrile, and relates to the technical field of organic synthesis. The new synthesis process for the 3-methoxyl-4-ethoxybenzonitrile comprises the following steps: taking ethyl vanillin as a raw material, taking N,N-dimethylformamide as a solvent, reacting the raw material and the solvent with potassium carbonate at first to form potassium salt, and reacting the obtained potassium salt with methyl iodide to obtain 3-methoxyl-4-ethoxy-benzaldehyde as an intermediate; adding hydroxylamine hydrochloride in a formic acid solution of the 3-methoxyl-4-ethoxy-benzaldehyde as the intermediate, heating and dehydrating, and carrying out desolventizing and recrystallization to obtain the high-purity 3-methoxyl-4-ethoxybenzonitrile finished product. The ethyl vanillin which is low in cost and is easily obtained as the raw material, aftertreatment operation is simple, and after being recycled, the N,N-dimethylformamide as the solvent can be directly used for other items; the 3-methoxyl-4-ethoxy-benzaldehyde as the intermediate are used for next reaction when not purified, so that purification cost is saved, and yield loss is avoided; and moreover, solid wastes are not produced in the whole process, and the total yield reaches 93.8%.
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Paragraph 0026; 0029; 0032; 0035
(2017/09/01)
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- Preparation method of Apremilast
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The invention relates to a preparation method of Apremilast, comprising the following steps: by taking 3-hydroxy-4-methoxybenzaldehyde as a staring material, reacting with hydroxylamine hydrochloride to obtain 3-hydroxy-4-methoxy cyanobenzene, reacting with bromoethane to obtain 3-ethyoxyl-4-methoxy cyanobenzene, and then reacting with dimethyl sulfone under the action of n-butyllithium, and hydrolyzing in aqueous hydrochloric acid solution to obtain 1-(3-ethyoxyl-4-methoxyphenyl)-2-(mesyl)ketol); finally by taking S-(-)-alpha, alpha-diphenyl-2-pyrrolidine methanol as a chiral catalyst and taking borane dimethyl sulfide complex solution as a reductant, obtaining chirality S-3-ethyoxyl-4-methoxy group-alpha[(mesyl)benzyl alcohol], and then reacting with 3-acetamido-phthalimide under the action of triphenylphosphine and diethyl azodicarboxylate, thus obtaining the Apremilast. According to the preparation method, the process is effectively simplified, the reaction conditions are mild, the product yield and purity are relatively high, and large-scale industrial production is benefited.
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Paragraph 0057; 0058
(2016/11/28)
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- Preparation method of chiral S/R-3-ethoxy-4-methoxy-alpha[(methylsulfonyl)methyl] benzyl alcohol
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The invention relates to a preparation method of chiral S/R-3-ethoxy-4-methoxy-alpha[(methylsulfonyl)methyl] benzyl alcohol. The preparation method comprises the following steps: 3-hydroxy-4-methoxybenzaldehyde is taken as a starting material and reacts with hydroxylammonium hydrochloride to produce 3-hydroxy-4-methoxybenzonitrile; 3-hydroxy-4-methoxybenzonitrile reacts with bromoethane to produce 3-ethoxy-4-methoxybenzonitrile; 3-ethoxy-4-methoxybenzonitrile reacts with dimethyl sulfone under the action of n-butyllithium, a product is hydrolyzed in an aqueous hydrochloric acid solution, and 1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanone is obtained; finally, S-(-)-alpha,alpha-diphenyl-2-pyrrolidinemethanol or R-(+)-alpha,alpha-diphenyl-2-pyrrolidinemethanol is taken as a chiral catalyst, a borane dimethyl sulfide solution is taken as a reducing agent, carbonyl is reduced, and a product is obtained. The reaction conditions are mild, the product yield is higher, the technology level is increased, the operability is improved, and large-scale industrial production is facilitated.
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Paragraph 0051; 0052
(2016/12/12)
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- PROCESS FOR THE ENANTIOMERIC RESOLUTION OF APREMILAST INTERMEDIATES
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A process for the resolution of racemic 2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine using novel chiral salts is disclosed. An L-phenylalanine p-toluene-sulfonamide salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine and a di-p-toluoyl-L-tartaric acid salt of (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine are also provided.
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Page/Page column 8
(2016/11/17)
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- Structure-activity relationship studies of SETD8 inhibitors
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SETD8 (also known as SET8, PR-SET7, or KMT5A (lysine methyltransferase 5A)) is the only known lysine methyltransferase that catalyzes the monomethylation of histone H4 lysine 20 (H4K20). In addition to H4K20, SETD8 monomethylates non-histone substrates such as the tumor suppressor p53 and the proliferating cell nuclear antigen (PCNA). Because of its role in regulating diverse biological processes, SETD8 has been pursued as a potential therapeutic target. We recently reported the first substrate-competitive SETD8 inhibitor, UNC0379 (1), which is selective for SETD8 over 15 other methyltransferases. We characterized this inhibitor in a battery of biochemical and biophysical assays. Here we describe our comprehensive structure-activity relationship (SAR) studies of this chemical series. In addition to 2- and 4-substituents, we extensively explored 6- and 7-substituents of the quinazoline scaffold. These SAR studies led to the discovery of several new compounds, which displayed similar potencies as compound 1 and interesting SAR trends. This journal is
- Ma, Anqi,Yu, Wenyu,Xiong, Yan,Butler, Kyle V.,Brown, Peter J.,Jin, Jian
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supporting information
p. 1892 - 1898
(2015/01/08)
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- Design and Synthesis of 3,5-Disubstituted-1,2,4-Oxadiazoles as Potent Inhibitors of Phosphodiesterase4B2
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A series of 3,5-disubstituted-1,2,4-oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition (PDE4B2). Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 9a is the most potent inhibitor (PDE4B2 IC50=5.28μm). Structure-activity relationship studies of 3,5-disubstituted-1,2,4-oxadiazoles revealed that substituents 3-cyclopentyloxy-4-methoxyphenyl group at 3-position and cyclic ring bearing heteroatoms at 5-position are important for activity. Molecular modeling study of the 3,5-disubstituted-1,2,4-oxadiazoles with PDE4B has shown similar interactions of 3-cyclopentyloxy-4-methoxyphenyl group; however, heteroatom ring is slightly deviating when compared to Piclamilast. 3-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (9a) exhibited good analgesic and antiinflammatory activities in formalin-induced pain in mice and carrageenan-induced paw edema model in rat.
- Kumar, Dalip,Patel, Gautam,Vijayakrishnan, Lalitha,Dastidar, Sunanda G.,Ray, Abhijit
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scheme or table
p. 810 - 818
(2012/06/18)
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- PROCESSES FOR THE PREPARATION OF AMINOSULFONE COMPOUNDS
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Processes for synthesizing aminosulfone compounds are provided. Aminosulfone compounds obtained using methods provided herein are useful in production or synthesis of isoindoline based PDE 4 modulators.
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Page/Page column 10
(2010/04/06)
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- Anthranilic acid derivatives as inhibitors of the cGMP-phosphodiesterase
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Compounds of formula (I) STR1where R 1 is hydrogen; R 2 is nitro, cyano or halo(lower)alkyl; R 3 is phenyl substituted with one or more substituents selected from halogen, cyano and lower alkoxy; A is a lower alkylene group; R 4 is a group CR 6 R 7 R 8 wherein R 6 and R 7 form, together with the carbon atom to which they are attached a cycloalkyl group optionally substituted with hydroxy, lower alkoxy or a lower alkanoylamino; and R 8 is hydrogen; its prodrug and a salt thereof.
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- Synthesis and Antitubercular Activity of 4-(5-Nitro-2-furyl/2-pyrazinyl/1-adamantyl)-2-(alkyl/aryl/arylamino)thiazoles
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The reaction of haloketones, obtained from Arndt-Eistert reaction on the acid chlorides of 1-adamantane, 5-nitrofuroic acid and pyrazine-2-carboxylic acid, with different thioamides and thioureas affords the title thiazoles (I-III).Some of them exhibit interesting antitubercular activity at 6.25 to 0.38 μg/ml concentration against H37Rv strain of M. tubercolosis in vitro testing.The structure activity relationship (SAR) has also been discussed.
- Khadse, B. G.,Lokhande, S. R.,Bhamaria, R. P.,Prabhu, S. R.
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p. 856 - 860
(2007/10/02)
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