KC-404: a potential anti-allergic agent with antagonistic action against slow reacting substance of anaphylaxis.
The mode of action of a novel compound, 3-isobutyryl-2-isopropylpyrazolo [1,5-a]pyridine (KC-404), as a potential anti-allergic agent has been investigated. KC-404 was shown to have a direct bronchodilator activity in guinea pig trachea in vitro and in anesthetized guinea pig in vivo. In addition, KC-404 had a fairly selective antagonistic action against slow reacting substance of anaphylaxis (SRS-A) on guinea pig ileum in vitro. In anesthetized guinea pigs, ED50 values for intravenously 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 to 0.1 mg/kg, also 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 sensitized guinea pig chopped lung in vitro at 10(-8) to 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 intraperitoneal doses of 2.5 to 10 mg/kg. The inhibitory activity on histamine release was less than half of that on SRS-A release. These results indicate that KC-404 is an orally active compound with a unique mode of action to inhibit preferentially both the effects and immunological release of SRS-A.
D000818:Animals; D001202:Ascitic Fluid / Q000166:cytology / Q000378:metabolism*; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects*; D007082:Ileum / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014132:Trachea / Q000187:drug effects*; D007212:Indolizines; D011720:Pyrazoles
D011725:Pyridines; D013189:SRS-A; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles