Vol. 298, Issue 3, 1142-1149, September 2001

Studies on Mechanisms of Low Emetogenicity of YM976, a Novel Phosphodiesterase Type 4 Inhibitor

Motonori Aoki, Masahiro Fukunaga, Tohru Sugimoto, Yasuno Hirano, Miki Kobayashi, Kazuo Honda and Toshimitsu Yamada

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

YM976 is a novel and selective inhibitor of phosphodiesterase type 4 (PDE4) with a different chemical structure from rolipram. Orally administered YM976 showed anti-inflammatory activity (ED₅₀ = 2.8 mg/kg) similar to rolipram (3.5 mg/kg). On the other hand, the emetogenicity of YM976, one of the main adverse effects of PDE4 inhibitors, was lower (maximal non-emetic dose = 10 mg/kg) than that of rolipram (1 mg/kg). The reasons for this low emetogenicity of YM976 remain unclear, and the present study endeavored to elucidate the mechanisms. Candidates for the possible mechanisms included 1) PDE4 subtype selectivity, 2) binding affinity for HAR-conformation, and 3) brain penetration. YM976 exhibited affinity for high affinity for rolipram-conformation (HAR-conformation) (IC₅₀ = 2.6 nM) identical to that of rolipram (1.2 nM), and failed to show significant selectivity for the individual PDE4 subtype. These results suggested that neither subtype selectivity nor the affinity for HAR-conformation may be related to the low emetogenicity of YM976. YM976 showed a minor effect on reserpine-induced hypothermia, in contrast to rolipram. To estimate brain penetration, we then measured cAMP contents in peripheral tissues (peritoneal macrophages) and in the brain. YM976 increased the cAMP content of peritoneal macrophages, but caused no significant increase in brain cAMP levels, while rolipram elevated the cAMP content of both tissues at the same dose. In conclusion, YM976 shows an apparent dissociation between its anti-inflammatory effects and emetogenicity, perhaps because of the poor brain penetration.