2,3-Dihydro-5-benzofuranols as antioxidant-based inhibitors of leukotriene biosynthesis.
The enzymes that catalyze the oxidative metabolism of arachidonic acid have provided fertile ground for the development of useful therapeutic agents for nearly a quarter century. Inhibitors of the enzyme cyclooxygenase prevent the formation of the prostaglandins and thromboxanes and are clinically useful antiinflammatories and peripheral analgesics. More recently it has been discovered that the enzyme 5-lipoxygenase is the first step in the formation of a series of biologically important metabolites of arachidonic acid, the leukotrienes. Evidence suggests that an inhibitor of 5-lipoxygenase may be a useful therapeutic agent in the treatment of asthma, immediate hypersensitivity, and inflammation. Various antioxidants have been examined as inhibitors of 5-lipoxygenase in vitro. We were intrigued by recent reports that the 2,3-dihydro-5-benzofuranol ring system maximizes the stereoelectronic effects necessary for efficient hydrogen atom abstraction by peroxyl radicals. In this study we describe the synthesis of over 50 new 2,3-dihydro-5-benzofuranols and their biological evaluation as inhibitors of leukotriene biosynthesis in isolated human polymorphonuclear leukocytes. We show that the 2,3-dihydro-5-benzofuranol ring system, although not a potent inhibitor of leukotriene biosynthesis in itself, can provide a useful template for the design of antioxidant-based inhibitors of leukotriene biosynthesis. Furthermore, within a structural class the potency of a given analogue can be predicted on the basis of its overall calculated lipophilicity (log P). The data are interpreted in terms of a model in which the observed inhibition by this class of inhibitors is dependent on the intrinsic ability of the antioxidant to reduce the enzyme and on the fraction of the inhibitor that is partitioned into the membrane.
Hammond
M L
ML
Department of Medicinal Chemistry-Immunology, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
Kopka
I E
IE
Zambias
R A
RA
Caldwell
C G
CG
Boger
J
J
Baker
F
F
Bach
T
T
Luell
S
S
MacIntyre
D E
DE
D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D001572:Benzofurans / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors; D012995:Solubility; D013329:Structure-Activity Relationship
D000975:Antioxidants; D001572:Benzofurans; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D001091:Arachidonate Lipoxygenases