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 (9c), 3-chloro (9d) and 3,4-dichloro (9e) benzoylamino-5-carbethoxymethyl-1,2,3,6-tetrahydropyridines, were synthesized and evaluated for their antiinflammatory activities. Antiinflammatory activities were screened in animal models employing carrageenan induced paw-edema assay on the male Sprague-Dawley 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. Relative potencies for inhibition of nitric oxide generation by macrophages stimulated with lipopolysaccharide (1 microgram/ml) were 1, 0.48, 0.44, 0.43, 0.45 and 0.45 for indomethacin (IC50 = 0.434 mM), 9a, 9b, 9c, 9d and 9e, respectively. The results show that novel tetrahydropyridines have moderate antiinflammatory activities and that they inhibit nitric oxide production by inhibiting inducible nitric oxide synthase.
Yoon
K
K
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee 32307, USA.
Wilson
T
T
Williams
S
S
Redda
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan / Q000633:toxicity; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011725:Pyridines; D009569:Nitric Oxide; D002351:Carrageenan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D007213:Indomethacin