Leukotrienes

This area of drug discovery has seen intense activity, and several orally active leukotriene (LT) antagonists have been clinically evaluated. A number of first-generation LTD4 antagonists were found to have an activity that was too weak to be effective in asthmatics [87]. Clinical studies showed that ICI 204,219 (30) when given orally, could reduce antigen-induced bronchocon-striction in asthmatic patients [88]. ICI 204,219 was reported to be a selective, competitive antagonist of LTD4-induced contractions of isolated human bronchioli and was effective in reversing LTD4-induced bronchocon-striction in a dose-dependent manner in guinea pigs by both oral and aerosol routes [89]. The styryl quinoliness (31a-31c) are another LTD4-receptor antagonist with good potential as antiasthmatic [90]. One of these, MK-571, is a recemic compound that has been evaluated as an inhibitor of LTD4-induced bronchoconstriction following intravenous administration to healthy volunteers and patients [91]. Development of the R-isomer of MK-679, which was selected for clinical evaluation based on preclinical in vitro and in vivo pharmacology, has been terminated due to poor tolerance. Compound RG 12525 (32), when dosed orally to mild asthmatics, was found to cause a 7.5fold shift in the dose response to inhaled LTD4 [92].

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