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

Drugs Exp Clin Res. 2000;26(3):73-82.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Carrageenan / toxicity
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Edema / chemically induced
  • Edema / drug therapy
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Indomethacin / pharmacology
  • Lipopolysaccharides / toxicity
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Magnetic Resonance Spectroscopy
  • Male
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase Type II
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Pyridines
  • Nitric Oxide
  • Carrageenan
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Indomethacin