Evaluation of LY163443, 1-[2-hydroxy-3-propyl-4-([4- (1H-tetrazol-5-ylmethyl)phenoxy]methyl) phenyl]ethanone, as a pharmacologic antagonist of leukotrienes D4 and E4.

Abstract

LY163443,1-[2-hydroxy-3-propyl-4-([4- (1H-tetrazol-5-ylmethyl)phenoxy]- phenoxy]methyl)phenyl]ethanone, antagonized LTD4-induced contractions of guinea pig ileum, trachea, and lung parenchyma. Tracheal contractions to LTE4 were also inhibited by LY163443. The compound had minimal effect against ileal responses to LTC4 and parenchymal contractions to LTB4. Furthermore, LY163443 had little to no effect against contractions of isolated smooth muscles to histamine, bradykinin, PGF2 alpha, carbachol, serotonin or U46619. LY163443, given by oral administration to guinea pigs, blocked LTD4-induced increases in total pulmonary impedance (TPI). Similar responses elicited by histamine or U46619 were unaffected. Increases in TPI in response to i.v. administration of LTC4 were antagonized by LY163443 given by the same route. Ovalbumin challenge also increased TPI in guinea pigs previously sensitized against this antigen. In such animals, pretreated with pyrilamine, propranolol, and indomethacin, oral administration of LY163443 blocked the increase in TPI caused by ovalbumin. Additionally, LTD4 given intradermally to guinea pigs caused a vascular leakage which was suppressed by prior oral administration of LY163443. Finally, LY163443 relaxed isolated guinea pig trachea previously contracted with LTD4, histamine, or carbachol. Relaxation of tissues contracted by these latter two agonists suggested some inherent airway smooth muscle relaxant properties of the molecule. This was further demonstrated by showing some bronchodilator activity in an in vivo setting. Thus, this pharmacologic profile indicates that LY163443, or a member of the same chemical family, warrants consideration as a possible therapeutic agent in the treatment of asthma and in diseases characterized by an overproduction of LTD4 and LTE4.