- Synergism of virtual screening and medicinal chemistry: Identification and optimization of allosteric antagonists of metabotropic glutamate receptor 1
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We report the identification of novel potent and selective metabotropic glutamate receptor 1 (mGluR1) antagonists by virtual screening and subsequent hit optimization. For ligand-based virtual screening, molecules were represented by a topological pharmacophore descriptor (CATS-2D) and clustered by a self-organizing map (SOM). The most promising compounds were tested in mGluR1 functional and binding assays. We identified a potent chemotype exhibiting selective antagonistic activity at mGluR1 (functional IC50 = 0.74 ± 0.29 μM). Hit optimization yielded lead structure 16 with an affinity of Ki = 0.024 ± 0.001 μM and greater than 1000-fold selectivity for mGluR1 versus mGluR5. Homology-based receptor modelling suggests a binding site compatible with previously reported mutation studies. Our study demonstrates the usefulness of ligand-based virtual screening for scaffold-hopping and rapid lead structure identification in early drug discovery projects.
- Noeske, Tobias,Trifanova, Dina,Kauss, Valerjans,Renner, Steffen,Parsons, Christopher G.,Schneider, Gisbert,Weil, Tanja
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- Synthesis and structure of [Na4(DMSO)15][(I 3)3(I)]. Self-assembly of hexacoordinated sodium
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A new complex with the molecular formula [Na4(DMSO) 15][(I3)3(I)] represents the first example of Na+ coordinated solely by DMSO. The triiodide (I3 -) and iodide (I-) anions form an infinite linear chain running throughout the crystal.
- Duarte-Ruiz, Alvaro,Nunez-Dallos, Nelson,Garzon-Tovar, Luis,Wurst, Klaus,Avella-Moreno, Eliseo,Gomez-Baquero, Fernando
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- Stereoselective Cyclopropanation of (-)-Levoglucosenone Derivatives Using Sulfonium and Sulfoxonium Ylides
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The synthesis of tri- and tetrasubstituted cyclopropanes from 3-aryl-substituted levoglucosenones (LGO) has been developed. In contrast to the unstabilised ylide dimethylsulfonium methylide which gives epoxides from LGO via 1,2-addition, we have found that the soft nucleophile dimethylsulfoxonium methylide affords cyclopropanes in moderate yields from LGO and in excellent yields and stereoselectivity with 3-aryl LGO derivatives. The use of 1,1,3,3-tetramethylguanidine as base in DMSO to generate the ylide provided the best yields and shortest reaction times. Ester stabilised sulfonium ylides could also be used to generate tetrasubstituted cyclopropane derivatives. One of the products was converted into a cyclopropyl lactone via Baeyer-Villiger oxidation to demonstrate the utility of applying cyclopropanation chemistry to LGO. Georg Thieme Verlag Stuttgart.New York.
- Ledingham, Edward T.,Merritt, Christopher J.,Sumby, Christopher J.,Taylor, Michelle K.,Greatrex, Ben W.
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- Deuterated antidepressant medicine
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The invention provides a compound represented by a structural formula I and a non-toxic pharmaceutically acceptable salt and use thereof in preparation of medicine for treatment of depression. In theformula I shown in the description, R1, R2, R3 and R4 are independent H or deuterium (D) separately, and meanwhile, at least one of the R1, R2, R3 and R4 must be D.
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Paragraph 0009-0010; 0013-014
(2019/01/23)
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- Preparation method of medetomidine and intermediate thereof
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The invention relates to a preparation method of 2-(2, 3-xylyl)-2-methyloxirane. The method is characterized in that the preparation process includes the following reaction shown as the specification, wherein Y is selected from Cl, Br, I, CH3SO4 or HSO4; alkali is selected from KOH, NaOH, LiOH, CsOH, K2CO3, Li2CO3, Cs2CO3, Na2CO3, EtONa, EtOK, (CH3)2CHONa, (CH3)2CHOK, (CH3)3CONa, (CH3)3COK, NH2Na or NH2K. The invention adopts the synthesis method using the 2-(2, 3-xylyl)-2-methyloxirane critical intermediate to prepare medetomidine.
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Paragraph 0064; 0065; 0066; 0067
(2017/08/28)
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- 1-[(4-HYDROXYPRIDIN-4-YL) METHYL]PYRIDINE-2(1H)-ONE DERIVATIVES, PREPARATION METHODS AND USES THEREOF
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Provided are N-[(4-hydroxypiperidin-4-yl)methyl]pyridin-2(1H)-one derivatives represented by formula I, stereoisomers, pharmaceutically acceptable salts or solvates thereof
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Paragraph 0064
(2013/03/28)
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- 1-[(4-hydroxypiperidin-4-yl)methyl]pyridin-2(1H)-one derivatives, preparation methods and uses thereof
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Provided are N-[(4-hydroxypiperidin-4-yl)methyl]pyridin-2(1H)-one derivatives represented by formula I, stereoisomers, pharmaceutically acceptable salts or solvates thereof. The above compounds have the dual activities of 5-hydroxytryptamine 1A receptor ligand and selective serotonin reuptake inhibitor. The preparation methods of the above compounds, the uses of these compounds for the prevention or treatment of nervous system diseases related to 5-hydroxytryptamine system dysfunction and the pharmaceutical compositions containing these compounds are also provided.
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Paragraph 0102
(2013/09/12)
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- A novel approach to enantiopure cyclopropane compounds from biotransformation of nitriles
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Rhodococcus sp. AJ270, a powerful and versatile nitrile hydratase/amidase containing microbial whole-cell system, catalyzed the enantioselective hydrolysis of both racemic trans- and cis-2-arylcyclopropanecarbonitriles to afford the corresponding amides and acids with enantiomeric excesses as high as >99%. The reaction rate and enantioselectivity observed for both nitrile hydratase and amidase were also strongly dependent upon the nature of the substituent and substitution pattern on the benzene ring of the substrates. The application of and the advantages of biotransformation of nitriles were demonstrated by preparing (1S,2R)-2-phenylcyclopropylamine and (1R,2R)-2-phenylcyclopropylmethylamine through facile and straightforward chemical manipulations of (1S,2S)-2-phenylcyclopropanecarboxylic acid and (1R,2R)-2-phenylcyclopropanecarboxamide, respectively.
- Wang, Mei-Xiang,Feng, Guo-Qiang
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p. 1575 - 1583
(2007/10/03)
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- An improved procedure for the methylation analysis of oligosaccharides and polysaccharides.
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An improved procedure for the methylation analysis of oligosaccharides and polysaccharides is described. Steps in the procedure were examined and optimised for quantitative recovery and speed. Methylation was shown to be complete by using [14C]methyl iodide. All operations were performed in the same tube and the need to concentrate solutions containing acetylated alditols of methylated sugars was eliminated, thus minimising losses due to volatilization. The method is convenient, gives high recoveries of acetylated alditols of methylated sugars, and allows analysis of the glycosyl linkages of oligo- or poly-saccharides to be completed within a working day. A wide range of oligo- and poly-saccharides were methylated by this procedure.
- Harris,Henry,Blakeney,Stone
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- 9-(2-Hydroxy-3-amino-propyl)-9,10-dihydro-9,10-ethano-anthracenes and salts thereof
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9-(2-A-3-R-propyl)-9,10-dihydro-9,10-ethanoanthracenes containing the nucleus of the formula STR1 wherein R denotes a secondary or tertiary amino group and A denotes a free, etherified or acylated hydroxyl group, their pharmaceutically acceptable salts are useful as psychotropics, especially as anti-depressants.
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- Production of carbonyl compounds substituted in α-position
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Production of carbonyl compounds substituted in the α-position and having the formula: EQU1 wherein R1 is alkyl, aralkyl, phenyl, toluyl, naphthyl, alkoxy or amino; R2 is hydrogen EQU2 A is hydrogen, alkyl, halo or EQU3 R6 is hydrogen or methyl, and R11 is alkyl; wherein said compounds are formed by reacting a sulfur ylide having the formula: EQU4 wherein Y is the radical EQU5 and R9 and R10 are alkyl or phenyl, with a solution containing both an electrophilic agent A' that is converted into the radical A and a nucleophilic agent B' that is converted into the radical B. The resulting carbonyl compounds are useful as starting materials for the production of paper, textile, and leather auxiliaries, plant protection agents, alkyd resins, polyesters and polyamides.
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