2,3-Dihydro-5-benzofuranols as antioxidant-based inhibitors of leukotriene biosynthesis

Abstract

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.

Inhibitory effect of olopatadine hydrochloride (KW-4679), a novel antiallergic drug, on peptide leukotriene release from human eosinophils

“…It has been reported that the antioxidant inhibits the production of LTB 4 in human neutrophils 11 . Ketotifen, at 100 μg/mL (235 μmol/L), is reported to exhibit a prominent radical‐scavenging effect in human neutrophils 12 .…”

Antipsoriatic Anthrones with Modulated Redox Properties. 3. 10-Thio-Substituted 1,8-Dihydroxy-9(10H)-anthracenones as Inhibitors of Keratinocyte Growth, 5-Lipoxygenase, and the Formation of 12(S)-HETE in Mouse Epidermis

“…Formation and release of arachidonic acid metabolites from PMNL 24 and keratinocytes 25 participate in amplifying the inflammatory response. [31][32][33][34][35] Anthralin itself is only a moderate 5-LO inhibitor. Accordingly, potential antipsoriatic drugs are evaluated for their ability to inhibit the production of LTB 4 .…”

Antipsoriatic anthrones with modulated redox properties. 1. Novel 10-substituted 1,8-dihydroxy-9(10H)-anthracenones as inhibitors of 5-lipoxygenase

“…23 Therefore, compounds with antioxidant properties would be expected to be potential inhibitors of 5-LO. [24][25][26][27][28] Furthermore, oxygen free radicals, which are inflammatory mediators of considerable importance, may be inactivated by such Compounds. 29 » 30 Although there have been attempts to develop new therapeutically effective derivatives of anthralin, such as triacetoxyanthracene 31 2 and butantrone 12 (3) for which initial reports were promising, later reports have indicated that these compounds were less effective and more irritating than anthralin itself.…”

“…In some studies on 5-LO inhibitors, relationships between the log of the octanol/ water partition coefficients (log P) and the structural changes resulting in increased activity were reported. 25 ' 26 ' 44 Thus, as a measure of lipophilicity, we determined the log P values of the new compounds by a standard HPLC procedure. 45 In our case, there was no clear relationship found between 5-LO inhibition and lipophilicity.…”