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5-[(3-Carboxy-4-hydroxyphenyl)diazenyl] nicotinic acid, an azo-linked mesalazine-nicotinic acid conjugate, is a colon-targeted mutual prodrug against dextran sulfate sodium-induced colitis in mice

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Abstract

Purpose

We aimed to develop a 5-aminosalicylic acid (5-ASA, mesalazine)-based anti-colitic drug with higher efficacy than sulfasalazine (SSZ), a colon-targeted prodrug of 5-ASA, for the treatment of inflammatory bowel disease (IBD). To this end, we synthesized a colon-targeted mutual prodrug (ASA-azo-NA) consisting of 5-ASA and the GPR109A agonist nicotinic acid, 5-[(3-carboxy-4-hydroxyphenyl)diazenyl] nicotinic acid.

Methods

In our previous study, oral gavage of ASA-azo-NA delivered 5-ASA and 5-aminonicotinic acid specifically to the large intestine in a 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat colitis model and ameliorated colonic damage and inflammation more effectively than oral SSZ. To increase the therapeutic convincibility of ASA-azo-NA for the treatment of IBD with multifactorial pathologies, the colon targetability and therapeutic activity of ASA-azo-NA were examined using a dextran sulfate sodium (DSS)-induced colitis mouse model with a different pathogenesis from that of DNBS-induced colitis in rats.

Results

ASA-azo-NA liberated 5-ASA in the cecal contents of mice while remaining stable in the small intestinal contents, with a cecal conversion rate and extent comparable to those of SSZ. Oral ASA-azo-NA and SSZ accumulated similar concentrations of 5-ASA in the cecum, indicating that ASA-azo-NA was delivered to and activated in the large intestine as efficiently as SSZ. In mice with DSS-induced colitis, oral ASA-azo-NA mitigated colonic damage and inflammation, as assessed using macroscopic and molecular indices, and was therapeutically superior to SSZ.

Conclusion

ASA-azo-NA acted as a colon-targeted mutual prodrug against DSS-induced mouse colitis. Thus, ASA-azo-NA may be therapeutically applicable to patients with IBD who are resistant to SSZ treatment.

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Acknowledgements

This work was supported by a 2-Year Research Grant of Pusan National University”.

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Authors and Affiliations

  1. College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea

    Seongkeun Jeong, Sanghyun Ju, Sohee Park & Yunjin Jung

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  1. Seongkeun Jeong
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  2. Sanghyun Ju
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  3. Sohee Park
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  4. Yunjin Jung
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Correspondence to Yunjin Jung.

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All institutional and national guidelines for the care and use of laboratory animals were followed. The animal study protocols used in this study were approved by the Institutional Animal Care and Use Committee of Pusan National University (Approval No: PNU-2017-1525).

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Jeong, S., Ju, S., Park, S. et al. 5-[(3-Carboxy-4-hydroxyphenyl)diazenyl] nicotinic acid, an azo-linked mesalazine-nicotinic acid conjugate, is a colon-targeted mutual prodrug against dextran sulfate sodium-induced colitis in mice. J. Pharm. Investig. 51, 317–325 (2021). https://doi.org/10.1007/s40005-021-00517-z

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  • DOI: https://doi.org/10.1007/s40005-021-00517-z

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