L-648,051, a novel cysteinyl-leukotriene antagonist is active by the inhaled route in man.

1. We have studied some of the pharmacological properties of inhaled L- 648,051 which has been shown to be a selective cysteinyl-leukotriene (LT) antagonist in vitro and in vivo in various animal models. 2. The effects of three different doses (1.6, 6.0 and 12.0 mg) on the bronchoconstriction induced by inhaled LTD4 have been investigated in normal male subjects in a series of double-blind, placebo controlled studies. Furthermore, the specificity of the drug has been investigated by challenging subjects with histamine after pre-inhalation of 12.0 mg L-648,051. 3. At all doses L-648,051 partially blocked the bronchoconstriction induced by LTD4 inhalation in a dose related manner. At a dose of 12.0 mg, L-648,051 decreased the maximum fall in specific airways conductance (sGaw) (placebo, 49% vs L-648,051, 21%, P less than 0.01) and shortened the time to recovery from LTD4-induced bronchoconstriction (placebo, 41 min vs L-648,051, 19 min, P less than 0.01). 4. There was no evidence of partial agonist activity, and no effect on histamine-induced bronchospasm. Inhaled L-648,051 at all doses was well tolerated. 5. We conclude that LT antagonism is possible by the inhaled route in man. Inhaled L-648,051 is an active and selective LT-antagonist in man which is well tolerated and may prove to be a useful drug for assessing the role of leukotrienes in asthma and other lung diseases.