The preclinical pharmacology of ICI 204,219. A peptide leukotriene antagonist.

ICI 204,219 (4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide) was designed as a peptide leukotriene (LT) antagonist. The compound is a competitive antagonist of LTD4- and LTE4-induced contraction of guinea pig lung tracheal and parenchymal strips with an apparent negative log molar dissociation constant (KB) of approximately 9.6. ICI 204,219 did not antagonize LTC4-induced contractions of guinea pig trachea when the metabolism of LTC4 to LTD4 and, subsequently, to LTE4 was inhibited. The compound inhibited the binding of [3H]LTD4, [3H]LTE4, and [3H]ICI 198,615 (a potent LT antagonist from a different heterocyclic series) to guinea pig lung parenchymal membranes in a competitive manner, and also inhibited [3H]ICI 198,615 binding to human lung parenchymal membranes. ICI 204,219 did not bind to a variety of other receptors when evaluated at concentrations 1,000- to 10,000-fold higher than the apparent KB value for peptide LT receptors. When administered orally,...