- Novel acid-type cyclooxygenase-2 inhibitors: Design, synthesis, and structure-activity relationship for anti-inflammatory drug
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Cyclooxygenase (COX) is a key rate-limiting enzyme for prostaglandin (PG) production cascades in the human body. The mechanisms of both the anti-inflammation effects and the side-effects of traditional COX inhibitors are associated with the existence of two COX isoforms. Thus while COX-1 is predominantly expressed ubiquitously and constitutively, and it serves a housekeeping role in processes such as gastrointestinal (GI) mucosa protection, COX-2 is absent or exhibits a low level of expression in most tissues, and is highly upregulated in response to endotoxin, virus, inflammatory or tissue-injury stimuli/signals, and tumour promoter in the various types of organs, tissues, and cells. Furthermore, COX-2 contribution to PGE2 and PGI2 production evokes and sustains systemic or peripheral inflammatory disease, but it is not involved in the COX-1-mediated GI tract events. Also, hypersensitivity of aspirin owing to its inhibitory action against COX-1 is a significant concern clinically. Consequently, highly selective COX-2 inhibitors have been needed for the treatment of inflammatory- and inflammation related-diseases that include pyrexia, inflammation, pain, rheumatoid arthritis, osteoarthritis, and cancers. In this study, a series of novel [2-{[(4-substituted or 4,5-disubstituted)-pyridin-2-yl]carbonyl}-(5- or 6-substituted or 5,6-disubstituted)-1H-indol-3-yl]acetic acid analogues was designed, synthesized, and evaluated to identify potent and selective COX-2 inhibitors as potential agents against inflammatory diseases. As significant findings, the present study clarified unique structure-activity relationship of the analogues toward potent and selective COX-2 inhibition in vitro, and identified 2-{6-fluoro-2-[4-methyl-2-pridinyl)carbonyl]-1H-indol-3-yl}acetic acid as a potent and selective COX-2 inhibitor in vitro that demonstrated orally potent anti-inflammation efficacy against carrageenan-induced oedema formation in the foot of SPF/VAF male SD rats as a peripheral inflammation model in vivo.
- Hayashi, Shigeo,Ueno, Naomi,Murase, Akio,Nakagawa, Yoko,Takada, Junji
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experimental part
p. 179 - 195
(2012/07/27)
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- Steric control of directional isomerism in dicopper(I) helicates of asymmetrically substituted 2,2':6',2':2,6'-quaterpyridine derivatives
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Derivatives of 2,2':6',2'':2'',6'''-quaterpyridine have been prepared which are asymmetrically substituted with alkyl groups in the 4- or 6- position and with various substituents in the 4'-position. These ligands form dicopper(I) double helicates which have been investigated by 1H and 13C NMR spectroscopic techniques. The formation of helical isomers is shown to depend on the intramolecular interactions between the constituent helicands of the double helicate; 4'-methyl substituents undergo steric interactions with the 4-substituent of the partner helicand, leading to a modest selectivity, although bulky 4-substituents decrease selectivity. In the absence of 4'-substituents, the smaller pitch permits steric interactions between like 4-substituents of the component helicands. In each case, formation of the head-to-head helicate isomer is preferred.
- Constable,Heirtzler,Neuburger,Zehnder
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p. 5606 - 5617
(2007/10/03)
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