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* = Presenting author

P099 Inhibitory effect of 6-aminopyridin-3-ol analogues on TNF-α-induced monocyte-colon epithelial cell adhesion and TNBS-induced rat colitis

B.-S. Jeong*1, S. Banskota1, P. Grung1, T.-g. Nam2, J.-A. Kim1

1Yeungnam University, College of Pharmacy, Gyeongsan, South Korea, 2Hanyang University, College of Pharmacy, Ansan, South Korea

Background

In inflammatory bowel disease (IBD), the balance between pro- and anti-inflammatory mediators is severely impaired and shifted towards the pro-inflammatory side. Pro-inflammatory cytokines such as tumour necrosis factor-α (TNF-α) and chemokines further recruit inflammatory cells to colon epithelium resulting in more inflammatory cytokine production and colonic tissue damage. IBD drugs such as corticosteroids, sulfasalazine (SSZ), and mesalazine (5-ASA) prevent the activation of NF-κB, a redox-dependent transcription factor, implicating protective effects of antioxidants on colitis. The present study aimed discovery of new and more potent drug candidate blocking inflammatory cytokine expression and colitis from 6-aminopyridin-3-ol derivatives, novel antioxidant chemicals.

Methods

The adhesion of U937 monocyte to HT-29 human colon cancer cell line was induced by TNF-α, which serves as an in-vitro model to screen inhibitory compounds. U937 cells were pre-labelled with BCECF-AM (10 μg/ml), and BCECF fluorescence was measured using a Fluostar Optima microplate reader using excitation at 485 nm of emission at 520 nm. In TNBS-induced rat colitis model, TNBS/ethanol solution was injected through rectum. The macroscopic ulceration and severity of colitis were evaluated in rat colon tissues.

Results

Compared with the activity of 20 mM 5-aminosalicylate (5-ASA), an active metabolite of SSZ, showing 46.8% inhibition against TNF-α-induced U937-HT29 adhesion, 5 6-aminopyridin-3-ol derivatives at 1 μM concentration inhibited the adhesion over 50%. In the IC50 measurement, 5-ASA showed 18.1 mM, 6-aminopyridin-3-ol derivatives including BJ-1119 showed IC50s ranging from 0.28 to 1.47 μM, implicating that 6-aminopyridin-3-ol derivatives were 10 000 times more potent than 5-ASA. Amongst the analogues, oral administration of BJ-1119, which showed the strongest in-vitro inhibitory activity, suppressed TNBS-induced rat colitis in a dose-dependent manner. In addition, the suppressive effect of 0.1 mg/kg BJ-1119 was similar to that of 300 mg/kg SSZ.

Conclusion

We found that 6-Aminopyridin-3-ol derivatives including BJ-1119 might be new and potent drug candidate for the treatment of IBD.