Peroxisome proliferator-activated receptor-γ mediates the anti-inflammatory effect of 3-hydroxy-4-pyridinecarboxylic acid derivatives: Synthesis and biological evaluation

Seven 3-hydroxy-4-pyridinecarboxylic acid derivatives (HPs), aza-analogues of salicylic acid and structurally close to other potent inflammatory pyridine compounds such as aminopyridinylmethanols and aminopyridinamines, were synthesized, and their anti-inflammatory activity was evaluated. The synthesis was performed by adopting a general procedure involving an intramolecular Diels–Alder cycloaddition of oxazoles with acrylic acid to form various substituted pyridinic acids. The newly synthesized HPs did not exhibit cytotoxic activity on human monocytes-derived macrophages at concentrations up to 102 μM. Anti-inflammatory activity of the compounds was screened in vitro by evaluating the capability to inhibit cytokines release from lipopolysaccharide (LPS) stimulated human macrophages. 3-Hydroxy-1-methyl-4-pyridinecarboxylic acid (24) was found to be the most active HP. At 10 μM concentration, HP 24 reduced LPS-induced and nuclear factor-κB activation and cyclooxygenase-2 expression, while increased intracellular reactive oxygen species generation and peroxisome proliferator-activated receptor (PPAR-γ) mRNA transcript level. Indeed, pre-treatment of LPS-exposed human macrophages with PPAR-γ specific antagonist completely prevented HP 24-induced TNF-α and IL8 down regulation, demonstrating that the PPARγ pathway is mandatory for the HP 24 anti-inflammatory effect. Finally, daily treatment with HP 24 ameliorated the outcome of DSS-induced colitis in mice, significantly reducing colonic MPO activity and IL-1β tissue levels.

Among the group of salicylic acid aza-analogues, 3-hydroxy-1-methyl-4-pyridinecarboxylic acid (24) showed to act by an anti-inflammatory effect mediated by peroxisome proliferator-activated receptor-γ. Preventive intragastric administration of HP 24 reduced colonic myeloperoxidase activity in DSS-induced colitis. The effect was similar to that of 5-ASA, widely used to treat patients with IBD.Figure optionsDownload as PowerPoint slideHighlights
► 3-Hydroxy-4-pyridinecarboxylic acids (HPs) were evaluated as anti-inflammatory agents.
► HP 24 reduces LPS-induced COX-2 and NF-κB protein expression.
► HP 24 increases intracellular ROS generation and PPAR-γ mRNA transcript level.
► HP 24-induced TNF-α and IL8 down regulation is prevented by PPAR-γ antagonist.
► Daily treatment with HP 24 ameliorates the outcome of DSS-induced colitis in mice.