ICI 204,219 (4-(5-cyclopentyloxycarbonylamino-1-methylindol-3-ylmethy l)-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, intravenously, or by
aerosol, the compound provided dose-related antagonism of the airway effects of
aerosol LTD4 in conscious guinea pigs. ED50 values and pharmacodynamic t1/2 (min) for oral, intravenous and
aerosol routes of administration were, respectively: 0.52 mumol/kg, greater than 816 min; 0.046 mumol/kg, 85 min; 5.1 x 10(-6) M, 109 min.
ICI 204,219 also produced dose-related inhibition of the effects of
LTC4 (
aerosol or
intravenous administration) on pulmonary mechanics in anesthetized guinea pigs when administered orally, intraduodenally, intravenously, or by
aerosol. The compound also reversed
bronchospasm produced by LTs.
Aerosol ovalbumin antigen-induced
bronchospasm in guinea pigs was both inhibited and reversed by
ICI 204,219. Lastly, the compound inhibited LTD4-induced increases in cutaneous vascular permeability in guinea pigs, being 1,006- and 679-fold more potent than the first generation LT antagonists LY 171,883 and
FPL 55712, respectively.
ICI 204,219 is a potent, selective, orally active LT antagonist currently undergoing clinical trials.