1 The effects of a novel anti-asthmatic drug, 3-isobutyryl-2-isopropylpyrazolo [1,5-a]pyridine (ibudilast, KC-404) on leukotriene D4 (LTD4)induced formation of inositol phosphates were studied in slices of guinea-pig lung and hippocampus.2 In guinea-pig lung, ibudilast inhibited LTD4 (0.01-1 uM)-induced formation of inositol monophosphate (IP1) in a concentration-dependent manner (IC5o = 10puM) without affecting LTD4 receptor binding. 3 Ibudilast (10pMm) inhibited histamine (0.1-1 mM)-induced formation of IP1 in guinea-pig lung slices but not in hippocampal slices. 4 Inhibition of agonist-induced formation of IP1 by ibudilast was non-competitive. 5 Ibudilast had no effect on either GTP-or calcium-stimulated phosphatidylinositol specificphospholipase C activity of lung membranes. 6 These results suggest that ibudilast has no direct effect on LTD4

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 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 antago nistic 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.

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