RG 12525 (5-(2-[4-quinolin-2-yl)methoxyl] phenoxymethyl)benzyl
tetrazole) is under investigation as a specific inhibitor of
leukotriene D4 (
LTD4). The present studies examine the effect of orally administered
RG 12525 on
LTD4 mediated pulmonary responses in three separate guinea pig models. The compound inhibited
antigen-induced mortality in the systemic
anaphylaxis model with an ED50 (95% confidence interval) = 2.2 (0.8-6.4) mg/kg. In this model, the activity half-life of
RG 12525 was shown to be 6.5 hours and the compound offered significant protection within 15 minutes of administration.
RG 12525 also protected against
LTD4-induced bronchoconstriction in a model measuring changes in pulmonary function with an ED50 = 0.6 (0.4-1.0) mg/kg. The same level of activity was observed in a similar model which monitored changes in pulmonary function in response to exogenous
antigen in actively-sensitized guinea pigs. Together, these data indicate that
RG 12525 is a potent, orally active
LTD4 antagonist which possesses the requisite profile for potential clinical development.