Synthesis and structure-activity relationships of a novel class of 5-lipoxygenase inhibitors. 2-(Phenylmethyl)-4-hydroxy-3,5-dialkylbenzofurans: the development of L-656,224.
The synthesis of a series of 2-(phenylmethyl)-4-hydroxy-3,5-dialkylbenzofurans and their inhibitory effects against leukotriene biosynthesis and 5-lipoxygenase activity in vitro are described. Many compounds in this series were found to be potent inhibitors of LTB4 production by human polymorphonuclear leukocytes with IC50 values ranging from 7 to 100 nM. Structure-activity relationships of the series are presented. Within this series, 2-[(4'-methoxyphenyl)methyl]-4-hydroxy-3-methyl-5-propyl-7-chlorobenz ofuran (L-656,224) showed extremely potent activity, inhibiting leukotriene biosynthesis in intact human leukocytes (IC50 = 11 nM), as well as the 5-lipoxygenase reaction catalyzed by cell-free preparations from rat leukocytes (IC50 = 36 nM), human leukocytes (IC50 = 0.4 microM), and the purified enzyme from porcine leukocytes (IC50 = 0.4 microM). The compound also shows oral activity in a number of animal models in vivo.
Lau
C K
CK
Department of Medicinal Chemistry, Merck Frosst Canada Inc., Pointe Claire-Dorval, Québec, Canada.
Bélanger
P C
PC
Scheigetz
J
J
Dufresne
C
C
Williams
H W
HW
Maycock
A L
AL
Guindon
Y
Y
Bach
T
T
Dallob
A L
AL
Denis
D
D
D000328:Adult; D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001572:Benzofurans / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001980:Bronchi; D055598:Chemical Phenomena; D002621:Chemistry; D003251:Constriction, Pathologic / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E; D007962:Leukocytes / Q000201:enzymology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000097:blood; D016859:Lipoxygenase Inhibitors; D015394:Molecular Structure; D009504:Neutrophils / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D001572:Benzofurans; D016859:Lipoxygenase Inhibitors; C055868:L 656224; D007975:Leukotriene B4; D007073:Immunoglobulin E; D001091:Arachidonate Lipoxygenases