- Inhibition of colitis by ring-modified analogues of 6-acetamido-2,4,5-trimethylpyridin-3-ol
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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.
- Chaudhary, Chhabi Lal,Chaudhary, Prakash,Dahal, Sadan,Bae, Dawon,Nam, Tae-gyu,Kim, Jung-Ae,Jeong, Byeong-Seon
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- Benzimidazole derivatives, their preparation and their therapeutic use
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Compounds of formula (I): STR1 [wherein: X represents an optionally substituted benzimidazole group; Y represents an oxygen or sulfur atom; Z represents a 2,4-dioxothiazolidin-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxooxazolidin-5-ylmethyl, 3,5-dioxooxadiazolidin-2-ylmethyl or N-hydroxyureidomethlyl group; R represents hydrogen, alkyl, alkoxy, halogen, hydroxy, nitro, amino or aralkyl; and m is an integer from 1 to 5]; have valuable activity for the treatment and/or prophylaxis of a variety of disorders, including one or more of: hyperlipemia, hyperglycemia, obesity, impaired glucose tolerance (IGT), insulin resistance and diabetic complications.
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- Treatment of arteriosclerosis and xanthoma
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A combination of one or more HMG-CoA reductase inhibitors (for example pravastatin, lovastatin, simvastatin, fluvastatin, rivastatin or atorvastatin) with one or more insulin sensitizers (for example troglitazone, pioglitazone, englitazone, BRL-49653, 5-(4-{2-?1-(4-2'-pyridylphenyl)ethylideneaminooxy!-ethoxy}benzyl)thiazolidine-2,4-dione, 5-{4-(5-methoxy-3-methylimidazo?5,4-b!pyridin-2-yl-methoxy)benzyl}thiazolidine-2,4-dione or its hydrochloride, 5-?4-(6-methoxy-l-methylbenzimidazol-2-ylmethoxy)benzyl!thiazolidine-2,4-dione, 5-?4-(l-methylbenzimidazol-2-ylmethoxy)benzyl!-thiazolidine-2,4-dione and 5-?4-(5-hydroxy-1,4,6,7-tetramethylbenzimidazol-2-ylmethoxy) benzyllthiazolidine-2,4-dione) exhibits a synergistic effect and is significantly better at preventing and/or treating arteriosclerosis and/or xanthoma than is either of the components of the combination alone.
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- ρ-heteroatom-substituted phenols and uses thereof
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The present invention provides an antiproliferative p-heteroatom-substituted phenol compound having the structure formula STR1 wherein m is 0 to 3, n is 0 to 4 when Het is nitrogen, wherein R is selected from the group consisting of hydrogen, alkyl, arylmethyl and acyl; R1 is alkyl; R2 is selected from the group consisting of hydrogen and alkyl; R3 is selected from the group consisting of alkyl and acyl when Het is nitrogen, R4 is selected from the group consisting of hydrogen and alkyl; R5 is selected from the group consisting of hydrogen and alkyl; and R6 and R7 are selected from the group consisting of hydrogen, alkyl and R6 and R7 together may represent oxygen. Also provided are various methods for the treatment of a pathological cell proliferative disease comprising administering to an animal) a pharmacologically and therapeutically effective dose of a pharmaceutical composition comprising a p-heteroatom-substituted phenols or an analog thereof.
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- Benzimidazole derivatives, their preparation and their therapeutic use
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Compounds of formula (I): [in which: X represents an optionally substituted benzimidazole group; Y represents an oxygen or sulphur atom; Z represents a 2,4-dioxothiazolidin-5-ylidenylmethyl, 2,4-dioxothiazolidin-5-ylmethyl, 2,4-dioxo-oxazolidin-5-ylmethyl, 3,5-dioxooxadiazolidin-2-ylmethyl or N-hydroxyureidomethyl group; R represents hydrogen, alkyl, alkoxy, halogen, hydroxy, nitro, amino or aralkyl; and mis an integer from 1 to 5]; have valuable activity for the treatment and/or prophylaxis of a variety of disorders, including one or more of: hyperlipemia, hyperglycemia, obesity, impaired glucose tolerance (IGT), insulin resistance and diabetic complications.
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