{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T12:45:50Z","timestamp":1763037950460,"version":"build-2065373602"},"reference-count":22,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T00:00:00Z","timestamp":1700092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea (NRF)","doi-asserted-by":"publisher","award":["2021R1I1A3A0403710411"],"award-info":[{"award-number":["2021R1I1A3A0403710411"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>In our previous study, riluzole azo-linked to salicylic acid (RAS) was prepared as a colon-targeted prodrug of riluzole (RLZ) to facilitate the repositioning of RLZ as an anticolitic drug. RAS is more effective against rat colitis than RLZ and sulfasalazine, currently used as an anti-inflammatory bowel disease drug. The aim of this study is to further improve colon specificity, anticolitic potency, and safety of RAS. N-succinylaspart-1-ylRLZ (SAR) and N-succinylglutam-1-ylRLZ (SGR) were synthesized and evaluated as a \u201cme-better\u201d colon-targeted prodrug of RLZ against rat colitis. SAR but not SGR was converted to RLZ in the cecal contents, whereas both conjugates remained intact in the small intestine. When comparing the colon specificity of SAR with that of RAS, the distribution coefficient and cell permeability of SAR were lower than those of RAS. In parallel, oral SAR delivered a greater amount of RLZ to the cecum of rats than oral RAS. In a DNBS-induced rat model of colitis, oral SAR mitigated colonic damage and inflammation and was more potent than oral RAS. Moreover, upon oral administration, SAR had a greater ability to limit the systemic absorption of RLZ than RAS, indicating a reduced risk of systemic side effects of SAR. Taken together, SAR may be a \u201cme-better\u201d colon-targeted prodrug of RLZ to improve the safety and anticolitic potency of RAS, an azo-type colon-targeted prodrug of RLZ.<\/jats:p>","DOI":"10.3390\/pharmaceutics15112638","type":"journal-article","created":{"date-parts":[[2023,11,17]],"date-time":"2023-11-17T00:49:47Z","timestamp":1700182187000},"page":"2638","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["N-Succinylaspartic-Acid-Conjugated Riluzole Is a Safe and Potent Colon-Targeted Prodrug of Riluzole against DNBS-Induced Rat Colitis"],"prefix":"10.3390","volume":"15","author":[{"given":"Jaejeong","family":"Kim","sequence":"first","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changyu","family":"Kang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5216-5518","authenticated-orcid":false,"given":"Jin-Wook","family":"Yoo","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0997-5723","authenticated-orcid":false,"given":"In-Soo","family":"Yoon","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunjin","family":"Jung","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/nature06005","article-title":"Unravelling the pathogenesis of inflammatory bowel disease","volume":"448","author":"Xavier","year":"2007","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.2174\/13816128113199990416","article-title":"Inflammatory bowel disease: Etiology, pathogenesis and current therapy","volume":"20","author":"Ko","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"90","DOI":"10.3109\/00365521.2014.968864","article-title":"Conventional drug therapy for inflammatory bowel disease","volume":"50","author":"Bryant","year":"2015","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S1734-1140(11)70575-8","article-title":"Treatment of inflammatory bowel disease (IBD)","volume":"63","author":"Pithadia","year":"2011","journal-title":"Pharmacol. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1038\/s41385-018-0050-3","article-title":"The current state of the art for biological therapies and new small molecules in inflammatory bowel disease","volume":"11","author":"Paramsothy","year":"2018","journal-title":"Mucosal Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1756283X17750355","DOI":"10.1177\/1756283X17750355","article-title":"Immunogenicity of biologics in inflammatory bowel disease","volume":"11","author":"Vermeire","year":"2018","journal-title":"Ther. Adv. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1056\/NEJMra1907607","article-title":"Newer Biologic and Small-Molecule Therapies for Inflammatory Bowel Disease","volume":"385","author":"Baumgart","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"215","DOI":"10.2147\/JIR.S165330","article-title":"Role of biologics and biosimilars in inflammatory bowel disease: Current trends and future perspectives","volume":"11","author":"Rawla","year":"2018","journal-title":"J. Inflamm. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Teruel, A.H., Gonzalez-Alvarez, I., Bermejo, M., Merino, V., Marcos, M.D., Sancenon, F., Gonzalez-Alvarez, M., and Martinez-Manez, R. (2020). New Insights of Oral Colonic Drug Delivery Systems for Inflammatory Bowel Disease Therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186502"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1615\/CritRevTherDrugCarrierSyst.v24.i2.20","article-title":"Therapeutic opportunities in colon-specific drug-delivery systems","volume":"24","author":"Patel","year":"2007","journal-title":"Crit. Rev. Ther. Drug Carrier Syst."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1023\/A:1011033121528","article-title":"Colonic drug delivery: Prodrug approach","volume":"18","author":"Sinha","year":"2001","journal-title":"Pharm. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/j.jconrel.2022.12.029","article-title":"Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics","volume":"353","author":"McCoubrey","year":"2023","journal-title":"J. Control. Release"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3784","DOI":"10.1021\/acs.molpharmaceut.2c00255","article-title":"A Colon-Targeted Prodrug of Riluzole Improves Therapeutic Effectiveness and Safety upon Drug Repositioning of Riluzole to an Anti-Colitic Drug","volume":"19","author":"Park","year":"2022","journal-title":"Mol. Pharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1002\/jps.23082","article-title":"N-succinylaspart-1-yl celecoxib is a potential colon-specific prodrug of celecoxib with improved therapeutic properties","volume":"101","author":"Lee","year":"2012","journal-title":"J. Pharm. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e12835","DOI":"10.1111\/jpi.12835","article-title":"N-Acetylserotonin is an oxidation-responsive activator of Nrf2 ameliorating colitis in rats","volume":"74","author":"Kang","year":"2023","journal-title":"J. Pineal Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.ejphar.2016.10.032","article-title":"The effect of memantine on trinitrobenzene sulfonic acid-induced ulcerative colitis in mice","volume":"793","author":"Motaghi","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.chembiol.2010.08.012","article-title":"Chemical-genetic screen identifies riluzole as an enhancer of Wnt\/beta-catenin signaling in melanoma","volume":"17","author":"Biechele","year":"2010","journal-title":"Chem. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"S233","DOI":"10.1212\/WNL.47.6_Suppl_4.233S","article-title":"The pharmacology and mechanism of action of riluzole","volume":"47","author":"Doble","year":"1996","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3259","DOI":"10.4049\/jimmunol.1701086","article-title":"Canonical Wnt Signaling in CD11c(+) APCs Regulates Microbiota-Induced Inflammation and Immune Cell Homeostasis in the Colon","volume":"200","author":"Swafford","year":"2018","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1136\/gut.27.8.886","article-title":"Transit of pharmaceutical dosage forms through the small intestine","volume":"27","author":"Davis","year":"1986","journal-title":"Gut"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105280","DOI":"10.1016\/j.ejps.2020.105280","article-title":"Impact of gastrointestinal physiology on drug absorption in special populations\u2014An UNGAP review","volume":"147","author":"Stillhart","year":"2020","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"253","DOI":"10.3109\/03602539109029761","article-title":"Metabolism of azo dyes: Implication for detoxication and activation","volume":"23","author":"Levine","year":"1991","journal-title":"Drug Metab. 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