KC-404: A potential anti-allergic agent with antagonistic action against slow reacting substance of anaphylaxis.

Publisher Website
Google Scholar
Abstract
The mode of action of a novel compound, 3-isobutyryl-2-isopropylpyrazolo [1,5-a]pyridine (KC-404), as a potential anti-allergic agent was investigated. KC-404 had a direct bronchodilator activity in a guinea-pig trachea in vitro and in am anesthetized guinea-pig in vivo. KC-404 had a fairly selective antagonistic action against a slow reacting substance of anaphylaxis (SRS-A) on guinea-pig ileum in vitro. In anesthetized guinea-pigs, ED50 values for i.v. and intraduodenally injected KC-404 to inhibit SRS-A-induced bronchoconstriction were 0.0014 and 0.0065 mg/kg, respectively. Much higher doses were required to inhibit bronchospasms produced by histamine or particularly by acetylcholine. Orally administered KC-404, 0.001-0.1 mg/kg, showed a selective inhibitory effect on increased vascular permeability by intradermal SRS-A in guinea-pigs and rats. KC-404 inhibited the immunological release of mediators, notably SRS-A from a sensitized guinea-pig chopped lung in vitro at 10-8-10-4 g/ml. In vivo, the release of SRS-A, but not of histamine, mediated by a nonreaginic antibody in the peritoneal cavity of sensitized rats was inhibited by KC-404 at oral doses above 3 mg/kg. In a similar anaphylactic reaction but mediated by a reaginic antibody, KC-404 also inhibited SRS-A release at i.p. doses of 2.5-10 mg/kg. The inhibitory activity on histamine release was less than 1/2 of that on SRS-A release. KC-404 is evidently an orally active compound with a unique mode of action to inhibit preferentially both the effects and immunological release of SRS-A.