In vitro and in vivo inhibitory activity of 6-amino-2,4,5-trimethylpyridin-3-ols against inflammatory bowel disease

Abstract

Although the pathogenesis of inflammatory bowel disease (IBD) is complex, attachment and infiltration of leukocytes to gut epithelium induced by pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) represents the initial step of inflammation in IBD. Previously, we have reported that some 6-amino-2,4,5-trimethylpyridin-3-ols have significant levels of antiangiogenic activity via PI3K inhibition. Based on the reports that angiogenesis is involved in the aggravation of IBD and that PI3K is a potential target for IBD therapy, we investigated whether the scaffold has inhibitory activity against in vitro and in vivo models of colitis. Many analogues showed >80% inhibition against TNF-alpha-induced monocyte adhesion to colon epithelial cells at 1 mu M. Compound 8m showed IC50 = 0.19 mu M, which is about five orders of magnitude better than that of 5-aminosalicylic acid (5-ASA, IC50 = 18.1 mM), a positive control. In a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, orally administered 8m dramatically ameliorated TNBS-induced colon inflammation. It was demonstrated by a high level of suppression in myeloperoxidase (MPO), a surrogate marker of colitis, as well as almost perfect recovery of colon and body weights in a dose-dependent manner. Compared to sulfasalazine, a prodrug of 5-ASA, compound 8m showed >300-fold better efficacy in those parameters. Taken together, 6-amino-2,4,5-trimethylpyridin-3-ols can provide a novel platform for anti-IBD drug discovery. (C) 2016 Elsevier Ltd. All rights reserved.