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

Abstract

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.

Inhibition by ibudilast of leukotriene D4‐induced formation of inositol phosphates in guinea‐pig lung

“…Mong et al, 1987b;Ahnfelt-R0nne et al, 1988). Ibudilast is a novel, orally active anti-asthmatic that is in clinical use (Nishino et al, 1983). The drug inhibits the increase in vascular permeability induced by antigen in sensitized guinea-pig airway smooth muscle (Eda et al, 1987) and antagonizes LTD4-induced contraction of guinea-pig lung parenchymal and tracheal strips (Ohasi et al, 1986).…”

Pharmacological Effect of KC-404 on Leukotriene Release from Human Leukocytes Induced by Ionophore A23187

“…KC-404 is shown to be a potent inhibitor of SRS-A released from guinea pig lung fragments [6] and a se lective antagonist of LTD4 [7], In addition to these anti-allergic actions, KC-404 has cerebrovasodilating activity and selectively increases vertebral blood flow when compared with femoral blood flow in anesthe tized dogs [12]. But there are no reports about the ef fect of KC-404 to the release of LTs.…”

“…According to reports, KC-404 prefe rentially inhibited SRS-A-induced contraction of isolated guinea pig ileum, SRS-A-induced bronchoconstriction in anesthetized guinea pig and SRS-A-induced increase in cutaneous vascular permeability in rats and guinea pigs [6]. Later it was suggested that KC-404 is a selective antagonist of LTD4 and that it interacts with LTD4 receptor in airway smooth mus cles but not in ileum [7,8].…”

“…Later it was suggested that KC-404 is a selective antagonist of LTD4 and that it interacts with LTD4 receptor in airway smooth mus cles but not in ileum [7,8]. KC-404 also inhibited the antigen-induced SRS-A release of lung and perito neal mast cells [6). However, there is no report con cerning what type of LT was inhibited.…”

Vasodilator Effects of Ibudilast on Retinal Blood Vessels in Anesthetized Rats

“…The clinical uses are based on the ability of ibudilast to relax airway smooth muscle, 13) attenuate allergic reaction, [13][14][15][16] inhibit the aggregation of platelets, 15,16) and increase cerebral blood flow [17][18][19][20] mainly through inhibition of phosphodiesterases (PDEs). 21,22) A previous study demonstrated that 2-week administration of ibudilast shortened the mean retinal circulation time in patients with diabetes mellitus.…”