A novel phosphodiesterase type 4 inhibitor, YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one), with little emetogenic activity

We synthesized a novel phosphodiesterase type 4 (PDE4) inhibitor, YM976, th at 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 ro lipram and RP73401 were 820 and 0.43 nM, respectively. Test compounds had n o effects on the other PDE isozymes, PDE1, -2, -3, and -5. YM976 potentiate d prostaglandin E-2-induced cAMP accumulation in a human mononuclear cell l ine, U937, and inhibited tumor necrosis factor-alpha production from human peripheral blood mononuclear cells stimulated by lipopolysaccharide. Anti-i nflammatory activities of PDE4 inhibitors were compared in rat carrageenan- induced pleurisy models. YM976, rolipram, and RP73401 inhibited the cell in filtration 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 rol ipram and RP73401 induced emesis at oral doses of 3 mg/kg. To evidence the dissociation of anti-inflammatory activity from emesis, the anti-inflammato ry 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 d oses 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.