Synthesis and pharmacological evaluations of N-(substituted benzoylamino)-5-carbethoxymethyl-1,2,3,6-tetrahydropyridines as potential antiinflammatory agents

In a continuing effort to enhance antiinflammatory activities, a series of 1,2,3,6-tetrahydropyridines, 4-tert butyl (9a), 4-methoxy (9b), 2-fluoro (9 c), 3-chloro (9d) and 3,4-dichloro (9e) benzoylamino-5-carbethoxymethyl- 1, 2,3,6-tetrahydropyridines, were synthesized and evaluated for their antiinf lammatory activities. Antiinflammatory activities were screened in animal m odels employing carrageenan induced paw-edema assay on the male Sprague-Daw ley rat. Relative potencies for carrageenan induced paw-edema assay were 1, 0.07, >0.03, 0.14, 0.4 and 0.12 for indomethacin (IC50 = 3 mg/kg), 9a, 9b, 9c, 9d and 9e, respectively. These novel tetrahydropyridines were assessed for nonsteroidal antiinflammatory drug-mediated inhibition of nitric oxide generation in RAW 264.7 macrophage cell line using Griess' reagent. Relati ve potencies for inhibition of nitric oxide generation by macrophages stimu lated with lipopolysaccharide (1 mu g/ml) were 1, 0.48, 0.44, 0.43, 0.45 an d 0.45 for indomethacin (IC50 = 0.434 mM), 9a, 9b, 9c, 9d and 9e, respectiv ely. The results show that novel tetrahydropyridines have moderate antiinfl ammatory activities and that they inhibit nitric oxide production by inhibi ting inducible nitric oxide synthase.