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

Title
In vitro and in vivo inhibitory activity of 6-amino-2,4,5-trimethylpyridin-3-ols against inflammatory bowel disease
Author
남태규
Keywords
6-Amino-2,4,5-trimethylpyridin-3-ol; Cell adhesion; Inflammatory bowel disease; TNBS-induced colitis; TNF-α
Issue Date
2016-10
Publisher
PERGAMON-ELSEVIER SCIENCE LTD
Citation
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, v. 26, No. 19, Page. 4587-4591
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.
URI
https://www.sciencedirect.com/science/article/pii/S0960894X16309076?via%3Dihubhttps://repository.hanyang.ac.kr/handle/20.500.11754/70860
ISSN
0960-894X; 1464-3405
DOI
10.1016/j.bmcl.2016.08.075
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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