In vitro and in vivo inhibitory activity of 6-amino-2,4,5-trimethylpyridin-3-ols against inflammatory bowel disease.
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-α (TNF-α) 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-α-induced monocyte adhesion to colon epithelial cells at 1μM. Compound 8m showed IC50=0.19μM, which is about five orders of magnitude better than that of 5-aminosalicylic acid (5-ASA, IC50=18.1mM), 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.
College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea.
Suhrid
S
Banskota
Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea.
Han-Eol
HE
Kang
College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea.
Dong-Guk
DG
Kim
Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea.
Sang Won
SW
Park
College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea.
Hyeonjin
H
Jang
College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea.
Ujjwala
U
Karmacharya
College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea. Electronic address: jeongb@ynu.ac.kr.
Byeong-Seon
BS
Jeong
College of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 38541, Republic of Korea. Electronic address: jakim@yu.ac.kr.
Jung-Ae
JA
Kim
Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea. Electronic address: tnam@hanyang.ac.kr.
Tae-Gyu
TG
Nam
D006801:Humans; D066298:In Vitro Techniques; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D011725:Pyridines / Q000737:chemistry* / Q000627:therapeutic use*
D011725:Pyridines
6-Amino-2,4,5-trimethylpyridin-3-ol; Cell adhesion; Inflammatory bowel disease; TNBS-induced colitis; TNF-α