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

• Published in: Journal of medicinal chemistry 1996-08, Vol.39 (16), p.3148-3157
• Main Authors: Hibi, Shigeki, Okamoto, Yasushi, Tagami, Katsuya, Numata, Hirotoshi, Kobayashi, Naoki, Shinoda, Masanobu, Kawahara, Tetsuya, Harada, Koukichi, Miyamoto, Kaname, Yamatsu, Isao
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Benzoquinones - chemical synthesis; Benzoquinones - pharmacology; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - enzymology; Bones, joints and connective tissue. Antiinflammatory agents; Cells, Cultured; Humans; Hydroxyurea - analogs & derivatives; Hydroxyurea - pharmacology; Leukotriene B4 - metabolism; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Methacrylates - pharmacology; Molecular Structure; Neutrophils - drug effects; Neutrophils - enzymology; Pharmacology. Drug treatments; Pyridines - chemical synthesis; Pyridines - pharmacology; Rats; Structure-Activity Relationship; Thromboxane B2 - metabolism; Thromboxane-A Synthase - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950725r

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 an 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.