The cysteinyl leukotrienes (CysLTs) LTC4 and LTD4 are potent mediators of asthma and hypersensitivity. They induce bronchoconstriction, increase microvascular permeability, and are vasoconstrictors of coronary arteries. Their biological effects are transduced by a pair of G protein-coupled receptors, CysLT1 and CysLT2. HAMI3379 is a potent cysteinyl leukotriene 2 (CysLT2) receptor antagonist that inhibits radioligand binding of LTD4 to CysLT2 and CysLT1 receptor cell lines with IC50 values of 37.9 and >30,000 nM, respectively. In a CysLT2 receptor reporter cell line, HAMI3379 antagonizes LTD4- and LTC4-induced intracellular calcium mobilization with IC50 values of 3.8 and 4.4 nM, respectively, whereas it only weakly inhibits that for a CysLT1 receptor reporter cell line (IC50 = >10,000 nM). In isolated Langendorff-perfused guinea pig hearts, HAMI3379 reverses the LTC4-stimulated increase in perfusion pressure and decrease in contractility.
