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5‑Aminosalicylic Acid Azo-Coupled with a GPR109A Agonist Is a Colon-Targeted Anticolitic Codrug with a Reduced Risk of Skin Toxicity
journal contribution
posted on 2019-12-03, 17:42 authored by Seongkeun Jeong, Hanju Lee, Soojin Kim, Sanghyun Ju, Wooseong Kim, Heeyeong Cho, Hyun Young Kim, Gwangbeom Heo, Eunok Im, Jin-Wook Yoo, In-Soo Yoon, Yunjin JungTo 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.
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NF -κB activationILrat colitis modelGPR 109A Agonistcolon-targeted 5- ASA prodrugGPR 109A antagonist5- ANAECNF -κB Oral ASA-azo-NA ameliorated rat colitisGPR 109A agonistSSZcolon-targeted anticolitic codrug5- ASA-based anti-inflammatory bowel disease drug5- ASA5- ASA azo-coupledcolon carcinoma cells62.7 μ MColon-Targeted Anticolitic Codrug
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