Pulmonary pharmacology of WAY-126299A: A dual-acting 5-lipoxygenase inhibitor and leukotriene D sub(4) antagonist

• Published in: Inflammation research 1995-01
• Format: Article
• Language: English
• ISSN: 1023-3830

Leukotrienes have been implicated in the pathogenesis of asthma. For this reason we previously sought a compound which could simultaneously act as a 5-lipoxygenase (5-LO) inhibitor and a leukotriene D sub(4) (LTD sub(4)) receptor antagonist. WY50295 tromethamine (WY-50295T) exhibited this unique dual mechanism of action in vitro and in vivo, including the inhibition of leukotriene production in human neutrophils, rat whole blood and guinea-pig lung fragments. However, WY-50295T was recently found to be inactive in human whole blood, presumably due to a high degree of plasma protein binding. Therefore, we subsequently sought to identify a compound which exhibited dual 5-LO inhibitory and LTD sub(4) antagonist activity, with oral potency and efficacy equivalent to WY-50295T in an animal model of asthma, which was also active in human whole blood. To our knowledge there are no compounds reported in the literature which exhibit 5-LO inhibitory activity in human whole blood and leukotriene antagonist activity. The present study compares WAY-126299A ((S)-6-(2-Benzothiazolylmethoxy)-N-hydroxy-alpha., N-dimethyl-2-naphthalene acetamide sodium salt) to WY-50295T and zileuton (a reference 5-LO inhibitor in development for the treatment of asthma).