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.
Footnotes
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Send reprint requests to: Motonori Aoki, Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd. 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. E-mail:aokim{at}yamanouchi.co.jp
- Abbreviations:
- PDE4
- phosphodiesterase type 4
- YM976
- 4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one
- LPS
- lipopolysaccharide
- TNF-α
- tumor necrosis factor-α
- PBMC
- peripheral blood mononuclear cells
- CIP
- carrageenan-induced pleurisy
- DMSO
- dimethyl sulfoxide
- FBS
- fetal bovine serum
- RT-PCR
- reverse transcription-polymerase chain reaction
- MC
- methylcellulose
- Received April 21, 2000.
- Accepted June 20, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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