- NOVEL HEPATITIS C VIRUS INHIBITORS
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The invention provides compounds of formula (I): wherein Rings A and A' are independently 5-membered optionally substituted aromatic heterocycles; Q is C(=O)NR1R1' or formula U is C(R4)2, O, S, S(=O)2, C(R4)2C(R4)2, CH2O, OCH2, CH2S, SCH2, CH2S(=O)2, S(=O)CH2 or C=C(Ru )2; X is CH2, CHR12, CR12R12, O, S, S(=O)2 or NRx; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; the other variables are as defined in the claims, which are of use in the treatment or prophylaxis of hepatitis C virus infection, and related aspects.
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- Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor
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A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1-/- mice.
- Zhao, Gang,Souers, Andrew J.,Voorbach, Martin,Falls, H. Doug,Droz, Brian,Brodjian, Sevan,Yau, Yi Lau,Iyengar, Rajesh R.,Gao, Ju,Judd, Andrew S.,Wagaw, Seble H.,Ravn, Matthew M.,Engstrom, Kenneth M.,Lynch, John K.,Mulhern, Mathew M.,Freeman, Jennifer,Dayton, Brian D.,Wang, Xiaojun,Grihalde, Nelson,Fry, Dennis,Beno, David W. A.,Marsh, Kennan C.,Su,Diaz, Gilbert J.,Collins, Christine A.,Sham, Hing,Reilly, Regina M.,Brune, Michael E.,Kym, Philip R.
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p. 380 - 383
(2008/09/17)
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- Ruthenium(salen)-catalyzed aerobic oxidative desymmetrizatin of meso-diols and its kinetics
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Chiral (nitrosyl)ruthenium(salen) complexes were found to be efficient catalysts for aerobic oxidative desymmetrization of meso-diols under photoirradiation to give optically active tactols. The scope of the applicability of this reaction ranges widely from acyclic diols to mono-cyclic diols, although fine ligand-tuning of the ruthenium(salen) complexes was required to attain high enantioselectivity (up to 93% ee). In particular, the nature of the apical ligand was found to affect not only enantioselectivity but also kinetics of the desymmetrization reaction. Spectroscopic analysis of the oxidation disclosed that irradiation of visible light is indispensable not only for dissociation of the nitrosyl ligand but also for single electron transfer from the alcohol-bound ruthenium ion to dioxygen.
- Shimizu, Hideki,Onitsuka, Satoaki,Egami, Hiromichi,Katsuki, Tsutomu
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p. 5396 - 5413
(2007/10/03)
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- Novel antifungal β-amino acids: Synthesis and activity against Candida albicans
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A series of novel β-amino acids has been synthesized and tested for their in vitro antifungal activity against Candida albicans. A steep SAR was observed. β-Amino acid 21 (BAY 10-8888/PLD-118) revealed the most favourable activity-tolerability profile and was selected for clinical studies as a novel antifungal for the oral treatment of yeast infections.
- Mittendorf, Joachim,Kunisch, Franz,Matzke, Michael,Militzer, Hans-Christian,Schmidt, Axel,Schoenfeld, Wolfgang
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p. 433 - 436
(2007/10/03)
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- Reactivity Patterns in the Rhodium Carbenoid Induced Tandem Cyclization-Cycloaddition Reaction
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The rhodium(II) acetate catalyzed behavior of ο--α-diazoacetophenone was studied.The results obtained are consistent with a mechanism in which the key step involves intramolecular cyclization of the ketocarbenoid onto the oxygen atom of the side chain to give an oxonium ylide intermediate which undergoes either C-H insertion or a competitive 2,3-sigmatropic rearrangement.The reaction of 1-diazo-9-decene-2,5-dione with rhodium(II) acetate results in cyclization of the intermediate rhodium carbenoid to give a six-ring carbonyl ylide which readily undergoes intramolecular dipolar cycloaddition.This reaction does not occur when the keto group of the diazo compound has been replaced by an ester functionality.Similar results were also obtained with cis-2-benzoyl-1-(diazoacetyl)cyclopentane.
- Padwa, Albert,Hornbuckle, Susan F.,Fryxell, Glen E.,Stull, Paul D.
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p. 817 - 824
(2007/10/02)
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- ENZYMATIC RESOLUTION OF RACEMIC BICYCLIC LACTONES BY HORSE LIVER ESTREASE
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Optically active lactones were prepared by Horse Liver esterase catalyzed hydrolysis of bicyclic γ-butyrolactones.
- Guibe-Jampel, E.,Rousseau, G.,Blanco, L.
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- A Study of Stereoselective Hydrolysis of Symmetrical Diesters with Pig Liver Esterase
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Pig liver esterase (PLE) catalyzed hydrolysis of dimethyl esters of symmetrical dicarboxylic acids, including meso-diacids, cis-1,2-cycloalkanedicarboxylic acids, and diacids with a prochiral center, was studied with 14 substrates.The products of these stereoselective hydrolyses are chiral monoesters of dicarboxylic acids, with an enantiomeric excess (e.e.) from 10percent to 100percent.Some of these optically active monoesters are valuable synthons in natural products synthesis.An additivity pattern of α- and β-substituents with the glutaric esters on the stereoselectivity of enzymatic hydrolysis was observed.Analysis of the experimental results leads to a model of enzyme stereoselectivity of diester hydrolysis in which the substitution pattern at α- and β-C-atoms is found to determine the absolute configuration of the resulting monoester.
- Mohr, Peter,Waespe-Sarcevic, Nada,Tamm, Christoph,Gawronska, Krystyna,Gawronsky, Jacek K.
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p. 2501 - 2511
(2007/10/02)
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- Thioalkanoylalkanoic acid compounds
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Thioalkanoylalkanoic acid compounds and salts thereof having the formula STR1 wherein R 1, R 2, R 3 and R 4 each is hydrogen or lower alkyl;R 5 is hydrogen, lower alkanoyl, benzoyl or STR2 A and B each is hydrogen or join together as a polymethylene chain --(CH 2) n -- to complete a 4-, 5- or 6- membered cycloalkyl group, and m is 0 or 1,are angiotensin converting enzyme inhibitors and are useful as hypotensive agents.
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