5-Aminosalicylic Acid Azo-Coupled with a GPR109A Agonist Is a Colon-Targeted Anticolitic Codrug with a Reduced Risk of Skin Toxicity.
To develop a 5-aminosalicylic acid (5-ASA)-based anticolitic drug with enhanced therapeutic activity, a colon-targeted codrug constituting 5-ASA and a GPR109A agonist was designed. 5-ASA azo-coupled with nicotinic acid (ASA-azo-NA) was synthesized, and the colon specificity and anticolitic effects were evaluated. Approximately 89% of ASA-azo-NA was converted to 5-aminonicotinic acid (5-ANA) and 5-ASA after 24 h of incubation in the cecal contents. 5-ANA was identified as a GPR109A agonist (concentration that gives half-maximal response (EC50): 18 μM) in a cell-based assay. Upon oral gavage of ASA-azo-NA (oral ASA-azo-NA) and sulfasalazine (oral SSZ), a colon-targeted 5-ASA prodrug, cecal accumulation of 5-ASA was comparable, and 5-ANA was barely detectable in the blood, while it was detected up to 62.7 μM with oral 5-ANA. In parallel, oral ASA-azo-NA did not elicit an adverse skin response. In murine macrophage and human colon carcinoma cells, activation of GPR109A by 5-ANA elevated the level of the anti-inflammatory cytokine IL-10, suppressed NF-κB activation, and potentiated the inhibitory activity of 5-ASA on NF-κB. Oral ASA-azo-NA ameliorated rat colitis and was more effective than oral SSZ, which were substantially blunted following cotreatment with the GPR109A antagonist, mepenzolate. In conclusion, ASA-azo-NA is a colon-targeted anticolitic codrug with a reduced risk of skin toxicity induced by the GPR109A agonist, therapeutically surpassing a current 5-ASA-based anti-inflammatory bowel disease drug in a rat colitis model.
['Jeong|Seongkeun|S|', 'Lee|Hanju|H|', 'Kim|Soojin|S|', 'Ju|Sanghyun|S|', 'Kim|Wooseong|W|', 'Cho|Heeyeong|H|', 'Kim|Hyun Young|HY|', 'Heo|Gwangbeom|G|', 'Im|Eunok|E|', 'Yoo|Jin-Wook|JW|', 'Yoon|In-Soo|IS|', 'Jung|Yunjin|Y|0000-0002-4794-483X']
D000818:Animals D000894:Anti-Inflammatory Agents, Non-Steroidal D045744:Cell Line, Tumor D002853:Chromatography, Liquid D003092:Colitis D003106:Colon D016503:Drug Delivery Systems D006801:Humans D015212:Inflammatory Bowel Diseases D016753:Interleukin-10 D008297:Male D019804:Mesalamine D051379:Mice D016328:NF-kappa B D009539:Nicotinic Acids D051381:Rats D017207:Rats, Sprague-Dawley D043562:Receptors, G-Protein-Coupled D012460:Sulfasalazine
5-aminosalicylic acid GPR109A codrug 5-aminonicotinic acid colon-targeted drug delivery inflammatory bowel disease