- Conversion of human-selective PPARα agonists to human/mouse dual agonists: A molecular modeling analysis
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To understand the species selectivity in a series of α-methyl- α-phenoxy carboxylic acid PPARα/γ dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARα. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARα leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARα agonist to a human and mouse dual agonist within the same platform.
- Wang, Minmin,Winneroski, Leonard L.,Ardecky, Robert J.,Babine, Robert E.,Brooks, Dawn A.,Etgen, Garret J.,Hutchison, Darrell R.,Kauffman, Raymond F.,Kunkel, Aaron,Mais, Dale E.,Montrose-Rafizadeh, Chahrzad,Ogilvie, Kathleen M.,Oldham, Brian A.,Peters, Mary K.,Rito, Christopher J.,Rungta, Deepa K.,Tripp, Allie E.,Wilson, Sarah B.,Xu, Yanping,Zink, Richard W.,McCarthy, James R.
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p. 6113 - 6116
(2007/10/03)
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- How Does Lipase Flexibility Affect Its Enantioselectivity in Organic Solvents? A Possible Role of CH...π Association in Stabilization of Enzyme-Substrate Complex
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For lipase-catalyzed reactions of 2-(4-substitued phenoxy)propionic acids with alcohols in organic solvents containing a small amount of water, the increase of the lipase flexibility brought about by addition of water is found to be favorable for the indu
- Watanabe, Keiichi,Uno, Tetsuya,Koshiba, Takashi,Okamoto, Takashi,Ebara, Yasuhito,Ueji, Shin-Ichi
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p. 543 - 548
(2007/10/03)
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- Oxazolyl-aryloxyacetic acid derivatives and their use as ppar agonists
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Novel compounds that are modulators of PPAR receptors, and pharmaceutically acceptable salts, solvates and hydrates thereof, processes for making the compounds, pharmaceutical compositions containing the compounds, or pharmaceutically acceptable salts, solvates and hydrates thereof.
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- Microbial deracemization of α-substituted carboxylic acids: Substrate specificity and mechanistic investigation
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A new enzymatic method for the preparation of optically active α-substituted carboxylic acids is reported. This technique is called deracemization reaction, which provides us with a route to obtain the enantiomerically pure compounds, theoretically in 100% yield starting from the racemic mixture. This means that the synthesis of a racemate is almost equal to the synthesis of the optically active compound, and this concept is entirely different from the commonly accepted one in the asymmetric synthesis. Using the growing cell system of Nocardia diaphanozonaria JCM3208, racemates of 2-aryl- and 2-aryloxypropanoic acid are deracemized smoothly and (R)-form-enriched products are recovered in high chemical yield (>50%). In addition, using optically active starting compounds and deuterated derivatives as well as inhibitors, we have disclosed the fact that a new type of enzyme takes part in this biotransformation, and that the reaction proceeds probably via the same mechanism as that in rat liver.
- Kato, Dai-Ichiro,Mitsuda, Satoshi,Ohta, Hiromichi
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p. 7234 - 7242
(2007/10/03)
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- Optical resolution of aryloxypropionic acids and their esters by HPLC on cellulose tris-3,5-dimethyl-triphenylcarbamate derivative
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Chiral chromatographic resolution of a series of antiphlogistic 2- aryloxypropionic acids and their methyl and ethyl esters was performed using a Chiralcel OD column. The CSP selected resolved most of the acids and esters efficiently, the enantiomers being well separated without requiring time consuming analysis. Chromatographic separation of R enriched samples was performed to determine the correct elution order. Using eluting systems such as hexane and 2-propanol, or hexane, 2-propanol and formic acid, the S enantiomer of all acids and esters was always found to elute first. We also considered the role of electron-donating or electron-withdrawing substituents (at the aryloxylic moiety) on the chiral resolution. It was shown that the electronic features of the substituents have more influence on the chiral interactions between the solutes and the CSP than their steric hindrance. Finally we determined, by molecular models, the interaction between CSP and solutes. In this way were able to determine all the potential sites for interactions, which are compatible with the conformations of the compounds and the structure of the stationary phase, and point out those interactions which enable chiral resolution.
- Azzolina,Collina,Ghislandi
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p. 1401 - 1416
(2007/10/02)
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- 2-[4-(4-Chlorophenoxymethyl)-phenoxy]-propionic acid compounds as herbicides
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Compounds of the formula STR1 wherein R1 and R2 are each hydrogen, chlorine or fluorine; and R3 is --CH2 OH, --CH2 --O--COR4, --CH2 --O--CONHR5, --COOH, --COOCat, --CO
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