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Synthesis and evaluation of 6-heteroarylamino-2,4,5-trimethylpyridin-3-ols as inhibitors of TNF-alpha-induced cell adhesion and inflammatory bowel disease

Title
Synthesis and evaluation of 6-heteroarylamino-2,4,5-trimethylpyridin-3-ols as inhibitors of TNF-alpha-induced cell adhesion and inflammatory bowel disease
Author
남태규
Keywords
INTESTINAL INFLAMMATION; THERAPEUTIC TARGETS; CROHNS-DISEASE; IBD; PATHOGENESIS6-AMINO-2,4,5-TRIMETHYLPYRIDIN-3-OLS; IL-10; ASSAY; RAT
Issue Date
2018-06
Publisher
ROYAL SOC CHEMISTRY
Citation
MED CHEM COMM, v. 9, No. 8, Page. 1305-1310
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal tract with complex pathogenesis. Here, we synthesized 6-heteroarylamino analogues to inhibit TNF-alpha-induced adhesion of monocytes to colon epithelial cells which are implicated in the initial inflammation process of IBD. The best analogue, 16a, showed IC50 = 0.29 mu M, which is about five orders of magnitude better than that of 5-aminosalicylic acid (5-ASA), a positive control. Oral administration of 6f and 16a dramatically ameliorated 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colon inflammation in rat. The ameliorating effects were accompanied by a high level of recovery in colon and body weights and in the myeloperoxidase (MPO) level. Consistently, the compounds suppressed the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1). Moreover, they significantly suppressed the expression of pro-inflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-6 while increasing the level of IL-10, an anti-inflammatory cytokine.
URI
https://pubs.rsc.org/en/content/articlehtml/2018/md/c8md00156ahttp://repository.hanyang.ac.kr/handle/20.500.11754/105580
ISSN
2040-2503
DOI
10.1039/c8md00156a
Appears in Collections:
COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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