Anti-inflammatory action of orally active 5-lipoxygenase inhibitor TMK688.

Abstract

A topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ear surface induces nonallergic inflammation, i.e. ear edema. Oral administration of 3-30 mg/kg of 1-([5'-(3"-methoxy-4"-ethoxycarbonyloxyphenyl)-2',4'-pentadieno yl]-aminoethyl)-4-diphenylmethoxypiperidine (TMK 688), a potent 5-lipoxygenase inhibitor with antihistamine activity, inhibited TPA-induced ear edema in a dose-dependent manner. TMK688 inhibited not only 5-lipoxygenase activity but also epidermal cyclooxygenase activity. 1-([5'-(3"-methoxy-4"-hydroxyphenyl)-2',4'-pentadienoyl]-aminoe thy l)- 4-diphenylmethoxypiperidine (TMK777), an active metabolite of TMK688, had more potent 5-lipoxygenase inhibitory activity but less potent cyclooxygenase inhibitory activity than TMK688. Oral administration of TMK688 (30 mg/kg) markedly inhibited TPA-stimulated LTB4 formation in mouse skin but TPA-stimulated PGE2 formation only slightly. Our experimental results suggest that both cyclooxygenase inhibitory activity and antihistamine activity of TMK688 are not essential to its anti-inflammatory action. The anti-inflammatory effect of orally administered TMK688 is due most probably to the anti-5-lipoxygenase activity of TMK688 and its active metabolite TMK777.

• Authors: S Yamamoto, H Jiang, R Kato
• Journal: Pharmacology (Pharmacology) Vol. 48 Issue 5 Pg. 273-82 (May 1994) ISSN: 0031-7012 [Print] Switzerland
• PMID: 8016188 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Cyclooxygenase Inhibitors
• Lipoxygenase Inhibitors
• Piperidines
• TMK 777
• TMK 688
• Leukotriene B4
• Dinoprostone
• Tetradecanoylphorbol Acetate

Topics

• Administration, Oral
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, pharmacology, therapeutic use)
• Cells, Cultured
• Cyclooxygenase Inhibitors
• Dermatitis, Contact (prevention & control)
• Dinoprostone (metabolism)
• Dose-Response Relationship, Drug
• Female
• Leukotriene B4 (metabolism)
• Lipoxygenase Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Mice
• Piperidines (administration & dosage, pharmacology, therapeutic use)
• Tetradecanoylphorbol Acetate