L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3- methyl-5-propyl-4-benzofuranol): a novel, selective, orally active 5-lipoxygenase inhibitor.
L-656,224 (7-chloro-2-[(4-methoxyphenyl)methyl]-3-methyl-5-propyl-4-benzofuranol) was a potent inhibitor of leukotriene biosynthesis in intact rat and human leukocytes and CXBG mastocytoma cells (IC50 values, 18-240 nM) and of crude human leukocyte and highly purified porcine leukocyte 5-lipoxygenase (IC50 value, 4 X 10(-7) M). The selectivity of L-656,224 for 5-lipoxygenase was shown through the relative lack of activity of the compound on 12-lipoxygenase, 15-lipoxygenase, cyclooxygenase, catalase, and myeloperoxidase. The compound showed (i) oral activity against hyperalgesia induced in the rat paw by injection of yeast or platelet-activating factor, (ii) dyspnea in sensitized inbred rats induced by an aerosol of antigen, and (iii) bronchoconstriction induced by an aerosol of Ascaris in squirrel monkeys, suggesting a role for 5-lipoxygenase inhibitors in the treatment of asthma and peripheral pain.
Belanger
P
P
Department of Medicinal Chemistry, Merck Frosst Canada Inc., Montréal, Qué.
Maycock
A
A
Guindon
Y
Y
Bach
T
T
Dollob
A L
AL
Dufresne
C
C
Ford-Hutchinson
A W
AW
Gale
P H
PH
Hopple
S
S
Lau
C K
CK
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001572:Benzofurans / Q000494:pharmacology*; D001792:Blood Platelets / Q000201:enzymology; D002374:Catalase / Q000037:antagonists & inhibitors; D002417:Cattle; D002478:Cells, Cultured; D004435:Eating / Q000187:drug effects; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000201:enzymology; D016859:Lipoxygenase Inhibitors; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D012453:Saimiri; D013025:Glycine max / Q000201:enzymology; D013045:Species Specificity; D013552:Swine
D001572:Benzofurans; D016859:Lipoxygenase Inhibitors; C055868:L 656224; D002374:Catalase; D009195:Peroxidase; D001091:Arachidonate Lipoxygenases; D011451:Prostaglandin-Endoperoxide Synthases