Bronchodilating effect of KC-404, a novel anti-asthmatic agent, and its derivatives in monkey.
The inhibitory effect of 3-isobutyryl-2-isopropylpyrazolo[1,5-alpha]pyridine (KC-404) on aerosolized methacholine- and histamine-induced increase in total respiratory resistance (Rrs) was determined in monkeys using the forced 3 Hz oscillation method and was compared with the effect of aminophylline. The effects of several derivatives of KC-404 on methacholine-induced bronchoconstriction were also determined. All of the i.v. administered pyrazolopyridine derivatives showed an inhibition of the increase in Rrs induced by aerosolized methacholine. Among these derivatives, KC-404 exerted the most potent bronchodilating effect. KC-404 also inhibited the histamine-induced increase in Rrs. These effects of KC-404 were more potent than those of aminophylline. On the other hand, the dose of KC-404 tested caused an increase in heart rate, although the degree was moderate as compared with aminophylline. From the results obtained in this study, it is considered that the pyrazolopyridine derivatives, particularly KC-404, may be promising bronchodilators for the treatment of bronchial asthma.
D000403:Airway Resistance / Q000187:drug effects; D000628:Aminophylline / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001993:Bronchodilator Agents; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D008251:Macaca; D008297:Male; D008688:Methacholine Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D007212:Indolizines; D011720:Pyrazoles
D000628:Aminophylline; D001993:Bronchodilator Agents; D006632:Histamine; D008688:Methacholine Compounds; D011725:Pyridines; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles