STRUCTURE-ACTIVITY-RELATIONSHIPS OF ,4-BENZOQUINONYL)-2-[(3-PYRIDYL)ALKYL]-2-PROPENOIC ACID-DERIVATIVES THAT INHIBIT BOTH 5-LIPOXYGENASE AND THROMBOXANE A(2) SYNTHETASE

As part of our research for the development of novel antiinflammatory drug candidates, we have designed and synthesized a series of ,4-benzo quinonyl)-2-[(3-pyridyl)alkyl]-2-propenoic acid derivatives as dual in hibitors of 5-lipoxygenase (5-LO) and thromboxane (TX) A(2) synthetase . In order to increase the absorption after oral administration, we in troduced 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 moiet y afforded good to moderate inhibitory activities against the producti on of leukotriene (LT) Bq and TXA(2) while not significantly inhibitin g that of prostaglandin E(2) by glycogen-induced peritoneal cells of r at (in vitro). The length of the methylene chain of the 3-pyridylalkyl group influenced the inhibition of LTB(4) and TXB(2) production. An i ncrease of lipophilicity by introducing a more lipophilic alkoxy group did not markedly increase the inhibitory activity on LTB(4) productio n. The position of an alkoxy group on the 1,4-benzoquinone skeleton pl ayed an important role in TXA(2) 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 ac id), showed good inhibition of both 5-LO and TXA(2) synthetase and pos sess a variety of pharmacologically beneficial effects.