1444336-77-9Relevant academic research and scientific papers
Synthesis and evaluation of 6-heteroarylamino-2,4,5-trimethylpyridin-3-ols as inhibitors of TNF-α-induced cell adhesion and inflammatory bowel disease
Park, Sang Won,Banskota, Suhrid,Gurung, Pallavi,Jin, You Jin,Kang, Han-eol,Chaudhary, Chhabi Lal,Lee, Sang Yeul,Jeong, Byeong-Seon,Kim, Jung-Ae,Nam, Tae-gyu
, p. 1305 - 1310 (2018)
Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal tract with complex pathogenesis. Here, we synthesized 6-heteroarylamino analogues to inhibit TNF-α-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 μM, 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-α, IL-1β, and IL-6 while increasing the level of IL-10, an anti-inflammatory cytokine.
Novel pyridine bioisostere of cabozantinib as a potent c-met kinase inhibitor: Synthesis and anti-tumor activity against hepatocellular carcinoma
Karmacharya, Ujjwala,Guragain, Diwakar,Chaudhary, Prakash,Jee, Jun-Goo,Kim, Jung-Ae,Jeong, Byeong-Seon
, (2021/09/10)
Two novel bioisosteres of cabozantinib, 3 and 4, were designed and synthesized. The ben-zene ring in the center of the cabozantinib structure was replaced by trimethylpyridine (3) and pyridine (4), respectively. Surprisingly, the two compounds showed extremely contrasting mesenchy-mal–epithelial transition factor (c-Met) inhibitory activities at 1 μM concentration (4% inhibition of 3 vs. 94% inhibition of 4). The IC50 value of compound 4 was 4.9 nM, similar to that of cabozantinib (5.4 nM). A ligand-based docking study suggested that 4 includes the preferred conformation for the binding to c-Met in the conformational ensemble, but 3 does not. The anti-proliferative activity of compound 4 against hepatocellular carcinoma (Hep3B and Huh7) and non-small-cell lung cancer (A549 and H1299) cell lines was better than that of cabozantinib, whereas 3 did not show a signifi-cant anti-proliferative activity. Moreover, the tumor selectivity of compound 4 toward hepatocellu-lar carcinoma cell lines was higher than that of cabozantinib. In the xenograft chick tumor model, compound 4 inhibited Hep3B tumor growth to a much greater extent than cabozantinib. The present study suggests that compound 4 may be a good therapeutic candidate against hepatocellular carci-noma.
Synthesis and activity of N-(5-hydroxy-3,4,6-trimethylpyridin-2-yl)acetamide analogues as anticolitis agents via dual inhibition of TNF-α- and IL-6-induced cell adhesions
Karmacharya, Ujjwala,Regmi, Sushil Chandra,Awasthi, Bhuwan Prasad,Chaudhary, Prakash,Kim, Ye Eun,Lee, Iyn-Hyang,Nam, Tae-gyu,Kim, Jung-Ae,Jeong, Byeong-Seon
supporting information, (2021/05/13)
Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are the critical pro-inflammatory cytokines involved in the pathogenesis of inflammatory bowel disease (IBD). Inhibition of these cytokines and related signaling pathways has been a target for the development of IBD therapeutics. In the current study, 6-acetamido-2,4,5-trimethylpyridin-3-ol (1) and various analogues with the amido scaffold were synthesized and examined for their inhibitory activities in in vitro and in vivo IBD models. The parent compound 1 (1 μM) showed an inhibitory activity against TNF-α- and IL-6-induced adhesion of monocytes to colon epithelial cells, which was similar to tofacitinib (1 μM), a JAK inhibitor, but much better than mesalazine (1,000 μM). All the analogues showed a positive relationship (R2 = 0.8943 in a linear regression model) between the inhibitory activities against TNF-α-induced and those against IL-6-induced adhesion. Compound 2–19 turned out to be the best analogue and showed much better inhibitory activity against TNF-α- and IL-6-induced adhesion of the cells than tofacitinib. In addition, oral administration of compound 1 and 2–19 resulted in a significant suppression of clinical signs of TNBS-induced rat colitis, including weight loss, colon tissue edema, and myeloperoxidase activity, a marker for inflammatory cell infiltration in colon tissues. More importantly, compound 2–19 (1 mg/kg) was more efficacious in ameliorating colitis than compound 1 and sulfasalazine (300 mg/kg), the commonly prescribed oral IBD drug. Taken together, the results suggest that compound 2–19 can be a novel platform for dual-acting IBD drug discovery targeting both TNF-α and IL-6 signaling.
Inhibition of colitis by ring-modified analogues of 6-acetamido-2,4,5-trimethylpyridin-3-ol
Chaudhary, Chhabi Lal,Chaudhary, Prakash,Dahal, Sadan,Bae, Dawon,Nam, Tae-gyu,Kim, Jung-Ae,Jeong, Byeong-Seon
, (2020/08/05)
6-Aminopyridin-3-ol scaffold has shown an excellent anti-inflammatory bowel disease activity. Various analogues with the scaffold were synthesized in pursuit of the diversity of side chains tethering on the C(6)-position. Structure-activity relationship among the analogues was investigated to understand the effects of the side chains and their linkers on their anti-inflammatory activities. In this study, structural modification moved beyond side chains on the C(6)-position and reached to pyridine ring itself. It expedited us to synthesize diverse ring-modified analogues of a representative pyridine-3-ol, 6-acetamido-2,4,5-trimethylpyridin-3-ol (9). In the evaluation of compounds on their inhibitory actions against TNF-α-induced adhesion of monocytic cells to colonic epithelial cells, an in vitro model mimicking colon inflammation, the effects of compounds 9, 17, and 19 were greater than tofacitinib, an orally available anti-colitis drug, and compound 17 showed the greatest activity. In addition, TNF-α-induced angiogenesis, which permits more inflammatory cell migration into inflamed tissues, was significantly blocked by compounds 17 and 19 in a concentration-dependent manner. In the comparison of in vivo therapeutic effects of compounds 9, 17, and 19 on dextran sulfate sodium (DSS)-induced colitis in mice, compound 17 was the most potent and efficacious, and compound 19 was better than compound 9 which showed a similar degree of inhibitory effect to tofacitinib. Taken together, it seems that either the trimethyl system or the hydroxyl group on the pyridinol ring is essential to the activity. This finding might become a new milestone in the development of pyridinol-based anti-inflammatory bowel disease agents.
PYRIDINOL DERIVATIVE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT
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, (2018/12/04)
The present invention relates to a pharmaceutical composition for preventing or treating inflammatory bowel disease, containing, as an active ingredient, a pyridinol derivative or a pharmaceutically acceptable salt thereof. A pyridinol derivative represented by chemical formula 1 or a pharmaceutically acceptable salt thereof has an excellent colitis inhibitory effect in an inflammatory bowel disease model, and thus can be useful as a medicine for preventing or treating inflammatory bowel disease.
Protective effects of 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols against 4-hydroxynonenal-induced cell death in adult retinal pigment epithelial-19 cells
Bae, Dawon,Gautam, Jaya,Jang, Hyeonjin,Banskota, Suhrid,Lee, Sang Yeul,Jeong, Min-Ji,Kim, A-Sol,Kim, Hong Chul,Lee, Iyn-Hyang,Nam, Tae-gyu,Kim, Jung-Ae,Jeong, Byeong-Seon
, p. 107 - 112 (2017/12/08)
Dysfunction or progressive degeneration of retinal pigment epithelium (RPE) contributes in the initial pathogenesis of age-related macular degeneration (AMD) causing irreversible vision loss, which makes RPE the prime target of the disease. The present study aimed to identify compounds to protect 4-hydroxynonenal (4-HNE)-induced RPE cell death by inhibiting NADPH oxidase 4 (NOX4) activity, not just as free radical scavengers, using ARPE-19, a human adult retinal pigment epithelial cell line, as a RPE representative. Novel thirty-two 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ol derivatives 17 were synthesized and tested. We found that there was a strong correlation between level of protective effect of compounds 17 against 4-HNE-induced APRE-19 cell death and that of inhibitory activity against 4-HNE-induced superoxide production, and that most of the compounds 17 showed minimal DPPH radical scavenging activity. Compound 17–28 showed the best protective activity against 4-HNE-induced superoxide production (79.5% inhibition) and cell death (85.1% recovery) at 10 μM concentration, which was better than that of VAS2870, a NOX2/4 inhibitor. In addition, compound 17–28 blocked 4-HNE-induced apoptosis of ARPE-19 cells in a concentration-dependent manner. The results indicate that compound 17–28 may be a lead compound to develop AMD therapeutics.
In vitro and in vivo inhibitory activity of 6-amino-2,4,5-trimethylpyridin-3-ols against inflammatory bowel disease
Banskota, Suhrid,Kang, Han-eol,Kim, Dong-Guk,Park, Sang Won,Jang, Hyeonjin,Karmacharya, Ujjwala,Jeong, Byeong-Seon,Kim, Jung-Ae,Nam, Tae-gyu
, p. 4587 - 4591 (2016/09/13)
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 1?μM. Compound 8m showed IC50?=?0.19?μM, 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.
AMIDOPYRIDINOL DERIVATIVE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING SAME AS ACTIVE COMPONENT
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Paragraph 0085; 0086, (2016/04/20)
The present invention relates to an amidopyridinol derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition including an amidopyridinol derivative or a pharmaceutically acceptable salt thereof as an active component. An amidopyridinol derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof has an excellent antiangiogenic effect in a chorioallantoic membrane model, and thus is useful as an agent for preventing or treating diseases associated with angiogenesis, such as macular degeneration or arthritis, and also has an excellent colitis-inhibitory effect in a model of inflammatory bowel diseases, and thus is useful as an agent for preventing or treating inflammatory bowel diseases. Upon inoculation of lung cancer cells in a chorioallantoic membrane model, the amidopyridinol derivative of Chemical Formula 1 or the pharmaceutically acceptable salt thereof inhibits angiogenesis and tumor growth that are caused by tumorigenesis, and also inhibits the activity of cathepsin S that plays an important role in metastasis and invasion of cancer, and thus is useful as an inhibitor of cancer growth and metastasis.
Pharmaceutical composition for preventing or treating cancer comprising amidopyridinol derivative or a pharmaceutically acceptable salt
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Paragraph 0036; 0067; 0068, (2016/10/27)
The present invention relates to an amidopyridinol derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition including an amidopyridinol derivative or a pharmaceutically acceptable salt thereof as an active component. An amidopyridinol derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof has an excellent antiangiogenic effect in a chorioallantoic membrane model, and thus is useful as an agent for preventing or treating diseases associated with angiogenesis, such as macular degeneration or arthritis, and also has an excellent colitis-inhibitory effect in a model of inflammatory bowel diseases, and thus is useful as an agent for preventing or treating inflammatory bowel diseases. Upon inoculation of lung cancer cells in a chorioallantoic membrane model, the amidopyridinol derivative of Chemical Formula 1 or the pharmaceutically acceptable salt thereof inhibits angiogenesis and tumor growth that are caused by tumorigenesis, and also inhibits the activity of cathepsin S that plays an important role in metastasis and invasion of cancer, and thus is useful as an inhibitor of cancer growth and metastasis.
6-Amino-2,4,5-trimethylpyridin-3-ols: A new general synthetic route and antiangiogenic activity
Kim, Dong-Guk,Kang, Youra,Lee, Hyunji,Lee, Eun Kyung,Nam, Tae-Gyu,Kim, Jung-Ae,Jeong, Byeong-Seon
, p. 126 - 139 (2014/04/17)
A new synthetic strategy for preparation of a wide range of 6-amino-2,4,5-trimethylpyridin-3-ols from pyridoxine·HCl via a six-step sequence has been developed. This approach features an introduction of various amino groups to C(6)-position of 3-benzyloxy-6-bromo-2,4,5-trimethylpyridine (13), a key intermediate, by a Buchwald-Hartwig amination reaction using palladium(0) transition metal, which certainly renders an expanded scope of amino substituents. Some analogs prepared using the methods described here showed high level of antiangiogenic and antitumor activities in chick chorioallantoic membrane (CAM) assay, demonstrating the potential of these new aminopyridinols as antiangiogenic agents.
