ChemInform Abstract: Structure-Activity Relationships of (E)-3-(1,4-Benzoquinonyl)-2-((3- pyridyl)alkyl)-2-propenoic Acid Derivatives That Inhibit Both 5- Lipoxygenase and Thromboxane A2 Synthetase

Autor: Naoki Kobayashi, Kokichi Harada, Yasushi Okamoto, Tetsuya Kawahara, Isao Yamatsu, Kaname Miyamoto, Katsuya Tagami, Numata Hirotoshi, Masanobu Shinoda, Shigeki Hibi
Rok vydání: 2010
Předmět:
Zdroj: ChemInform. 27
ISSN: 0931-7597
DOI: 10.1002/chin.199648146
Popis: As part of our research for the development of novel antiinflammatory drug candidates, we have designed and synthesized a series of (E)-3-(1,4-benzoquinonyl)-2-[(3-pyridyl)alkyl]-2-propenoic acid derivatives as dual inhibitors of 5-lipoxygenase (5-LO) and thromboxane (TX) A2 synthetase. In order to increase the absorption after oral administration, we introduced a carboxylic acid moiety into the 1,4-benzoquinone skeleton, which has 5-LO-inhibitory character. Introduction of a 3-pyridylalkyl group at the double bond of the 1,4-benzoquinonyl propenoic acid moiety afforded good to moderate inhibitory activities against the production of leukotriene (LT) B4 and TXA2 while not significantly inhibiting that of prostaglandin E2 by glycogen-induced peritoneal cells of rat (in vitro). The length of the methylene chain of the 3-pyridylalkyl group influenced the inhibition of LTB4 and TXB2 production. An increase of lipophilicity by introducing a more lipophilic alkoxy group did not markedly increase the inhibitory activity on LTB4 production. The position of alkoxy group on the 1,4-benzoquinone skeleton played an important role in TXA2 synthetase inhibition. Compounds such as 20c (E6700) with an appropriate alkoxy group and proper length of methylene side chain, together with a polar substituent (carboxylic acid), showed good inhibition of both 5-LO and TXA2 synthetase and possess a variety of pharmacologically beneficial effects.
Databáze: OpenAIRE
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