Vol. 297, Issue 1, 165-173, April 2001

Antiasthmatic Effect of YM976, a Novel PDE4 Inhibitor, in Guinea Pigs

Motonori Aoki, Satoshi Yamamoto, Miki Kobayashi, Keiko Ohga, Hiroyuki Kanoh, Keiji Miyata, Kazuo Honda and Toshimitsu Yamada

Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba-shi, Ibaraki, Japan

YM976 is a novel and specific phosphodiesterase 4 inhibitor. In our previous report, we indicated that YM976 has less emetogenicity, a major adverse effect of PDE4 inhibitors, than rolipram. In the present study, we examined the antiasthmatic effects of YM976 in guinea pigs. YM976 orally administered exhibited inhibition of antigen-induced bronchoconstriction, airway plasma leakage, airway eosinophil infiltration, and airway hyperreactivity (AHR), with ED₅₀ values of 7.3, 5.7, 1.0, and 0.52 mg/kg, respectively. Rolipram also dose dependently suppressed these responses. Prednisolone suppressed eosinophil infiltration and AHR, whereas it failed to inhibit bronchoconstriction and plasma leakage. Theophylline moderately suppressed bronchoconstriction and edema, but neither eosinophil infiltration nor AHR. YM976 suppressed the peroxidase activity in the bronchoalveolar lavage fluid, and elevated the intracellular peroxidase activity and cAMP contents of infiltrated cells, suggesting that YM976 inhibited not only the infiltration but also the activation of leukocytes. In vitro studies revealed that YM976 potently suppressed eosinophil activation (EC₃₀ = 83 nM), and exerted a little relaxation on LTD₄-precontracted tracheal smooth muscle (EC₅₀ = 370 nM). Rolipram exhibited a potent tracheal relaxation activity (EC₅₀ = 50 nM). In vivo studies indicated that the inhibitory effect of YM976 on LTD₄-induced bronchospasm was marginal even at 30 mg/kg p.o., although rolipram significantly inhibited the bronchospasm at the same dose. These results suggested that YM976, unlike rolipram, showed the inhibition of antigen-induced airway responses due to anti-inflammatory effects, but not to direct tracheal relaxation. In conclusion, YM976 may have potential therapeutic value in the treatment of asthma through its anti-inflammatory activities.