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 IC(50) of 2.2 nM. IC(50) 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 E(2)-induced cAMP accumulation in a human mononuclear cell line, U937, and inhibited
tumor necrosis factor-alpha 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 ED(30) 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.