L-648,051, a potent and specific aerosol active leukotriene D4 antagonist.

L-648,051 (I) is a potent, competitive and selective antagonist of the leukotriene D4 receptor in guinea pig and human lung tissue. Its activity on isolated smooth muscle preparations and its superiority relative to other agents (L-649,923 (II) or FPL 55712) in reversing ongoing contraction to LTD4 was somewhat unexpected in light of the results of receptor binding studies (Ki = 6.2 microM for L-648,051 versus 0.4 microM for L-649,923 and 2.0 microM for FPL 55712 on guinea pig lung membranes). The reasons for this observed superiority are unknown but may relate to the rate at which various antagonists equilibrate with the leukotriene receptors on various tissues. The physical properties (polarity) of L-648,051 may contribute to this enhanced rate of equilibration. The rapid metabolism and elimination of L-648,051 in vivo should be an advantage for a topical agent by minimizing systemic exposure. The potential role for L-648,051 as a novel aerosol therapy for asthma is now being investigated.