Pharmacologic actions of the second generation leukotriene B-4 receptor antagonist LY293111: in vivo pulmonary studies

We examined the in vivo actions of LY293111 sodium (2-[2-propyl-3-[3-[2-eth yl-4-(4-fluorophenyl)5-hydroxyphenoxy]propoxy]phenoxy] benzoic acid sodium salt). Guinea pigs were used to evaluate the effect of this agent on (1) ac ute airway obstruction produced by intravenous leukotriene B-4, (2) pulmona ry granulocyte infiltration and delayed onset airway obstruction resulting from a 4-h leukotriene B-4 inhalation and (3) lung inflammation after aeros ol challenge with the divalent cationic ionophore A23187 (6S-[6 alpha(2S*,3 S*),8 beta(R*),9 beta,11 alpha]-5-(methylamino)-2-[[3,9,11-trimethyl-8-[1-m ethyl-2-oxo-2(1H-pyrrol-2-yl)ethyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4 -benzoxazolecarboxylic acid). Airway obstruction was quantitated using pulm onary gas trapping measurements and lung inflammation was evaluated by bron choalveolar lavage (BAL) and histology. LY293111 sodium produced a dose-rel ated inhibition of acute leukotriene B-4-induced airway obstruction when ad ministered i.v. (ED50=14 mu g/kg) or p.o. (ED50=0.4 mg/kg). In contrast, LY 293111 sodium did not inhibit the pulmonary gas trapping caused by aerosols of histamine, leukotriene D-4, or the thromboxane mimetic U46619 (15 [(S)- hydroxy-11a,9a-(epoxymethano)prosta-5Z,13E-dienoic acid]). Oral LY293111 so dium inhibited leukotriene B-4-induced bronchoalveolar lavage granulocyte i nfiltration and delayed onset airway obstruction at doses as low as 0.3 mg/ kg. In A23187-challenged animals, pulmonary inflammation was markedly inhib ited at 1 h, but not 2 h and 4 h post-exposure. We conclude that LY293111 s odium is a selective leukotriene B-4 receptor antagonist with potent pulmon ary anti-inflammatory activity.