Abstract

We synthesized a novel phosphodiesterase type 4 (PDE4) inhibitor, YM976, that is structurally different from the other PDE4 inhibitors like rolipram. In the present study, the pharmacological profile of YM976 was investigated. YM976 exhibited a strong and competitive inhibition against PDE4 purified from human peripheral leukocytes with an IC₅₀ of 2.2 nM. IC₅₀ values of rolipram and RP73401 were 820 and 0.43 nM, respectively. Test compounds had no effects on the other PDE isozymes, PDE1, -2, -3, and -5. YM976 potentiated prostaglandin E₂-induced cAMP accumulation in a human mononuclear cell line, U937, and inhibited tumor necrosis factor-α production from human peripheral blood mononuclear cells stimulated by lipopolysaccharide. Anti-inflammatory activities of PDE4 inhibitors were compared in rat carrageenan-induced pleurisy models. YM976, rolipram, and RP73401 inhibited the cell infiltration into the pleural cavity with oral ED₃₀ values of 9.1, 10, and 7.4 mg/kg, respectively. YM976 produced no emesis up to 10 mg/kg, whereas rolipram and RP73401 induced emesis at oral doses of 3 mg/kg. To evidence the dissociation of anti-inflammatory activity from emesis, the anti-inflammatory effect of YM976 was examined in ferrets. YM976 dose dependently reduced carrageenan-induced leukocyte infiltration at the doses of 1, 3, and 10 mg/kg, p.o. On the other hand, rolipram failed to show obvious inhibition at doses that do not induce emesis. In conclusion, YM976 is a novel and orally active PDE4 inhibitor and possesses a good separation of emetogenicity from anti-inflammatory activity.