In Vitro Pharmacology of ICI 198,61 5: A Novel, Potent and Selective Peptide Leukotriene Antagonist1

IC, 1 98,61 5 is a representative compound from a new dass of peptide leukotriene (LT) receptor antagonists. In isolated guinea-pig trachea and parenchymal lung strips, ICI 1 98,61 5 demon-strated competitive antagonism of the contractile activity of LTD4 and LTE. with pA2 values of 1 0.1 to 9.5, respectively. The compound also appeared to antagonize the contractile activity of LTC4 in guinea pig trachea; however, in the presence of an inhibitor of the metabolism of LTC4 to LTD4, ICI 198, 615 provided a pI value of 5.3, indicating weak antagonism at the LTC4 receptor. ICI 1 98,61 5 was also a potent antagonist of LTC4 and LTD4 in isolated human bronchi and pulmonary veins with pI values of 9.75 ± 0.32 to 9.20 ± 0.24, respectively. When evaluated for aCtivity on a broad vanety of non-LT receptors, the compound displayed a minimal selectivity of 631 0 and a maximal selectivity of> 125,000 for the LTE. receptor. These in vitro studies indicate that PCI 1 98,61 5 is the most potent and selective peptide LT receptor antagonist deSCribed to date. Peptide LTs C4, D4, and E4 are potent constrictors of airway smooth muscle in several species, including humans (Drazen e