Mediator release inhibitor

The chromone cromolyn sodium (5-5) was at one time considered the forerunner of a novel class of antiallergic and antiasthmatic drugs that act at one of the earliest stages of the allergic reaction. Detailed experiments, acmally conducted after the dmg s clinical effectiveness had been confirmed, suggested that the compound inhibited the release of mediators of the allergic reaction from mast cells. The dmg is not very active when taken orally and is usually applied topically to the lung by insufflation as its sodium salt. Considerable efforts to uncover additional structurally related mediator release inhibitors have had only limited success. 

The dibenzopyranone ring system may be viewed as a chromone with an additional fused benzene ring and thus generally related to the antiasthmatic mediator release inhibitor cromolyn (see Chapter 11). Two dibenzopyranones have in fact been investigated for this indication in the clinic. Friedel-Crafts cyclization of the substituted cresyloxybenzoic acid (2-1) in sulfuric acid leads to the dibenzopyranone (2-2). The methyl group is then oxidized to a carboxylic acid by means of chromic acid. The acid is then converted to its sodium salt, xanoxate sodium (2-3) [2]. 

The mediator release inhibitors 460 and 461 were shown to inhibit human leucocyte alkaline phosphatase noncompetitively. As substituents, methyl, isopropyl, and methoxy were found optimal for460, and methyl and isopropyl for 461. 

Mediator Release Inhibitors (MRI) - A comprehensive review of this class of compounds has appeared recently. Non-linear regression analysis of a series of 51 drugs active in the rat PCA assay revealed that both the conformation of a drug and its capacity to act as an electron acceptor in charge-transfer interactions were critical for high activity. Studies continue to elucidate the mode of action of the prototype MRI, disodium cromoglycate (DSCG) and a comprehensive review of the... 

Cromoglycate appeared to have, then, what at the time was a completely novel mode of action which has given us the title of this Symposium - Mediator Release Inhibitors. This type of action quickly became known as antiallergic activity, a term which increasingly became familiar to medicinal chemists during the 1970 s. 

Mediator release inhibitors with antihistamine activity Several agents which are both antihistamines and inhibitors of mediator release have also been reported (Figure 12). An early compound of this type was Schering 15,280 (C, azanator) (76). Three other compounds (Cl, Cll and ClII) have subsequently been reported (TJ-SI). The most advanced of these is ketotifen (Cl) which is structurally related to azanator. It is orally active in man at 1 mg (b.i.d.) (Z7) and has been marketed by Sandoz in Switzerland. Two other potent, orally active compounds in the rat PCA procedure are Janssen s oxatomide (7 ,79) and Boehringer Mannheim s BM 15,100 (S0>S1)- These compounds combine the properties of mediator release inhibition with antihistamine activity. 

The second section of this book deals with such drugs, which may block mediator release, but also act to inhibit the consequences of mediator release or other bronchospastic stimulation. Such drugs could then provide therapeutic utility beyond the often incomplete prophylactic actions of mediator release inhibitors. 

They do not exhibit the cardiac stimulatory properties of theophylline. In addition, to bronchodilator action, compound II possesses, as predicted from its tricyclic structure, antihlstamlnlc and possibly even some mediator release inhibitor properties which could compliment its overall utility in allergic airways disease. 

These "pure mediator release Inhibitors" are discussed elsewhere in this symposium. 

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