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.
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.
Hibi
S
S
Tsukuba Research Laboratories, Eisai Company Ltd., Ibaraki, Japan.
Okamoto
Y
Y
Tagami
K
K
Numata
H
H
Kobayashi
N
N
Shinoda
M
M
Kawahara
T
T
Harada
K
K
Miyamoto
K
K
Yamatsu
I
I
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016227:Benzoquinones / Q000138:chemical synthesis* / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008689:Methacrylates / Q000494:pharmacology; D015394:Molecular Structure; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013929:Thromboxane B2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016227:Benzoquinones; D016859:Lipoxygenase Inhibitors; D008689:Methacrylates; D011725:Pyridines; D007975:Leukotriene B4; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase; C034364:ozagrel; C063449:zileuton; D006918:Hydroxyurea