{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:16:01Z","timestamp":1793146561824,"version":"4.5.0"},"reference-count":54,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T00:00:00Z","timestamp":1687824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation (DFG)","award":["SPP1656"],"award-info":[{"award-number":["SPP1656"]}]},{"name":"German Research Foundation (DFG)","award":["TRR241"],"award-info":[{"award-number":["TRR241"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Biologicals have dominated the therapeutic scenery in inflammatory bowel diseases (IBDs), namely ulcerative colitis (UC) and Crohn\u2019s disease (CD), for the past 20 years. The development of tofacitinib was the starting point for an era of small molecules after the era of biologicals. These new agents may challenge the use of biological agents in the future. They share properties that appeal to both patients and physicians. Low production costs, a lack of immunogenicity, and ease of use are only some of their benefits. On the other hand, patients and their physicians must manage the potential side effects of small molecules such as JAK inhibitors or S1P1R modulators. Here, we present agents that have already entered the clinical routine and those that are still being investigated in clinical trials.<\/jats:p>","DOI":"10.3390\/cells12131730","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:33:07Z","timestamp":1687912387000},"page":"1730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Novel Small Molecules in IBD: Current State and Future Perspectives"],"prefix":"10.3390","volume":"12","author":[{"given":"Andr\u00e9","family":"Jefremow","sequence":"first","affiliation":[{"name":"Department of Medicine 1, University Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"},{"name":"Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany"},{"name":"Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus F.","family":"Neurath","sequence":"additional","affiliation":[{"name":"Department of Medicine 1, University Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"},{"name":"Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany"},{"name":"Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1159\/000500721","article-title":"Mechanism-Based Treatment Strategies for IBD: Cytokines, Cell Adhesion Molecules, JAK Inhibitors, Gut Flora, and More","volume":"4","author":"Schreiner","year":"2019","journal-title":"Inflamm. Intest. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1056\/NEJMoa050516","article-title":"Infliximab for induction and maintenance therapy for ulcerative colitis","volume":"353","author":"Rutgeerts","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1016\/S0140-6736(02)08512-4","article-title":"Manteniance infliximab in Crohn\u2019s disease: The ACCENT I randomised trial","volume":"359","author":"Hanauer","year":"2002","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101763","DOI":"10.1016\/j.bpg.2021.101763","article-title":"New agents for immunosuppression","volume":"54\u201355","author":"Jefremow","year":"2021","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1111\/den.13863","article-title":"The endoscopic diagnosis of mucosal healing and deep remission in inflammatory bowel disease","volume":"33","author":"Moriichi","year":"2021","journal-title":"Dig. Endosc."},{"key":"ref_6","unstructured":"Colombel, J., Louis, E., Peyrin-Biroulet, L., Sandborn, W., and Panaccione, R. (2023, May 11). The Classical Immunosuppression: Overrated or Underused?. Available online: https:\/\/www.semanticscholar.org\/paper\/The-Classical-Immunosuppression-%3A-Overrated-or-Deep-Colombel-Louis\/cb5488f1c06df425f7248fe76d4f01bf65cac45f?p2df."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s11894-013-0315-7","article-title":"Deep remission in inflammatory bowel disease: Looking beyond symptoms","volume":"15","author":"Zallot","year":"2013","journal-title":"Curr. Gastroenterol. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1093\/ecco-jcc\/jjy004","article-title":"Primary non-response to tumor necrosis factor antagonists is associated with inferior response to second-line biologics in patients with Inflammatory bowel diseases: A systematic review and meta-analysis","volume":"12","author":"Singh","year":"2018","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1097\/MIB.0000000000000202","article-title":"Role for therapeutic drug monitoring during induction therapy with TNF antagonists in IBD: Evolution in the definition and management of primary nonresponse","volume":"21","author":"Papamichael","year":"2015","journal-title":"Inflamm Bowel Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00535-017-1324-3","article-title":"Systematic review with meta-analysis: Loss of response and requirement of anti-TNF\u03b1 dose intensification in Crohn\u2019s disease","volume":"52","author":"Qiu","year":"2017","journal-title":"J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/apt.16723","article-title":"Trends in the use of biologicals and their treatment outcomes among patients with inflammatory bowel diseases\u2014A Danish nationwide cohort study","volume":"55","author":"Zhao","year":"2022","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"175628482311594","DOI":"10.1177\/17562848231159452","article-title":"Is there an optimal sequence of biologic therapies for inflammatory bowel disease?","volume":"16","author":"Bressler","year":"2023","journal-title":"Ther. Adv. Gastroenterol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"517","DOI":"10.3389\/fmed.2020.00517","article-title":"Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF?","volume":"7","author":"Atreya","year":"2020","journal-title":"Front. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.addr.2012.09.019","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"64","author":"Lipinski","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1016\/j.drudis.2022.02.015","article-title":"Small molecules and their impact in drug discovery: A perspective on the occasion of the 125th anniversary of the Bayer Chemical Research Laboratory","volume":"27","author":"Beck","year":"2022","journal-title":"Drug. Discov. Today"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1159\/000527422","article-title":"New and Emerging Treatments for Inflammatory Bowel Disease","volume":"104","author":"Higashiyama","year":"2023","journal-title":"Digestion"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"651415","DOI":"10.3389\/fphar.2021.651415","article-title":"Novel and Emerging Therapies for Inflammatory Bowel Disease","volume":"12","author":"Shivashankar","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Caiazzo, G., Caiazzo, A., Napolitano, M., Megna, M., Potestio, L., Fornaro, L., Parisi, M., Luciano, M.A., Ruggiero, A., and Testa, A. (2023). The Use of JAK\/STAT Inhibitors in Chronic Inflammatory Disorders. J. Clin. Med., 12.","DOI":"10.3390\/jcm12082865"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1038\/ng.764","article-title":"Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47","volume":"43","author":"Anderson","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/ng.175","article-title":"Genome-wide association defines more than 30 distinct susceptibility loci for Crohn\u2019s disease","volume":"40","author":"Barrett","year":"2008","journal-title":"Nat. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1056\/NEJMoa1112168","article-title":"Study A3921063 Investigators.. Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis","volume":"367","author":"Sandborn","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1056\/NEJMoa1606910","article-title":"Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis","volume":"376","author":"Sandborn","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1136\/gutjnl-2016-312735","article-title":"Tofacitinib for induction and maintenance therapy of Crohn\u2019s disease: Results of two phase IIb randomised placebo-controlled trials","volume":"66","author":"Sandborn","year":"2017","journal-title":"Gut"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1016\/S0140-6736(21)00666-8","article-title":"Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): A phase 2b\/3 double-blind, randomised, placebo-controlled trial","volume":"397","author":"Feagan","year":"2021","journal-title":"Lancet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2139","DOI":"10.1053\/j.gastro.2020.02.030","article-title":"Efficacy of Upadacitinib in a Randomized Trial of Patients with Active Ulcerative Colitis","volume":"158","author":"Sandborn","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1056\/NEJMoa2212728","article-title":"Upadacitinib Induction and Maintenance Therapy for Crohn\u2019s Disease","volume":"388","author":"Loftus","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1053\/j.gastro.2015.08.044","article-title":"Safety and Efficacy of AJM300, an Oral Antagonist of \u03b14 Integrin, in Induction Therapy for Patients with Active Ulcerative Colitis","volume":"149","author":"Yoshimura","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1111\/j.1365-2036.2006.02837.x","article-title":"Safety and efficacy of two dose formulations of alicaforsen enema compared with mesalazine enema for treatment of mild to moderate left-sided ulcerative colitis: A randomized, double-blind, active-controlled trial","volume":"23","author":"Miner","year":"2006","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1053\/j.gastro.2019.10.035","article-title":"Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients with Ulcerative Colitis","volume":"158","author":"Sandborn","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/S0140-6736(23)00061-2","article-title":"Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): Two randomised, double-blind, placebo-controlled, phase 3 studies","volume":"401","author":"Sandborn","year":"2023","journal-title":"Lancet"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1016\/S0140-6736(22)00581-5","article-title":"Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: Results from three phase 3, multicentre, double-blind, randomised trials","volume":"399","author":"Danese","year":"2022","journal-title":"Lancet"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1053\/j.gastro.2020.01.047","article-title":"Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients with Crohn\u2019s Disease","volume":"158","author":"Sandborn","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1093\/ecco-jcc\/jjaa049","article-title":"Development of gut-selective pan-janus kinase inhibitor TD-1473 for ulcerative colitis: A translational medicine programme","volume":"14","author":"Sandborn","year":"2020","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1093\/ecco-jcc\/jjw103","article-title":"Clinical effects of a topically applied toll-like receptor 9 agonist in active moderate-to-severe ulcerative colitis","volume":"10","author":"Atreya","year":"2016","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_35","first-page":"1063","article-title":"Cobitolimod for moderate-to-severe, left-sided ulcerative colitis (CONDUCT): A phase 2b randomised, double-blind, placebo-controlled, dose-ranging induction trial. Lancet Gastroenterol","volume":"5","author":"Atreya","year":"2020","journal-title":"Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e533","DOI":"10.1016\/j.crohns.2013.03.014","article-title":"Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice","volume":"7","author":"Sugiura","year":"2013","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/S2468-1253(22)00022-X","article-title":"AJM300 (carotegrast methyl), an oral antagonist of \u03b14-integrin, as induction therapy for patients with moderately active ulcerative colitis: A multicentre, randomised, double-blind, placebo-controlled, phase 3 study","volume":"7","author":"Matsuoka","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1111\/j.1365-2036.2006.02910.x","article-title":"A Phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis","volume":"23","author":"Wedel","year":"2006","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1136\/gut.2003.036160","article-title":"A randomised, controlled, double blind, escalating dose study of alicaforsen enema in active ulcerative colitis","volume":"53","year":"2004","journal-title":"Gut"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/j.1365-2036.2004.01863.x","article-title":"An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis","volume":"19","author":"Miner","year":"2004","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1056\/NEJMoa1513248","article-title":"Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis","volume":"374","author":"Sandborn","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1056\/NEJMoa2033617","article-title":"Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis","volume":"385","author":"Sandborn","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/S2468-1253(20)30188-6","article-title":"Ozanimod induction therapy for patients with moderate to severe Crohn\u2019s disease: A single-arm, phase 2, prospective observer-blinded endpoint study","volume":"5","author":"Sandborn","year":"2020","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1093\/ecco-jcc\/jjab232.023","article-title":"A phase II, Multicentre, Randomised, Double-Blind, Placebo-controlled Study to Evaluate Safety, Tolerability, and Efficacy of Amiselimod in Patients with Moderate to Severe Active Crohn\u2019s Disease","volume":"16","author":"Danese","year":"2022","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2526","DOI":"10.1016\/j.cgh.2019.12.032","article-title":"Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients with Active Ulcerative Colitis","volume":"18","author":"Danese","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12977-015-0159-3","article-title":"Long lasting control of viral rebound with a new drug ABX464 targeting Rev\u2013mediated viral RNA biogenesis","volume":"12","author":"Campos","year":"2015","journal-title":"Retrovirology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4860","DOI":"10.1038\/s41598-017-04071-3","article-title":"The Anti-Hiv Candidate Abx464 Dampens Intestinal Inflammation by Triggering Il-22 Production in Activated Macrophages","volume":"7","author":"Chebli","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1038\/s41598-018-37813-y","article-title":"Both anti-inflammatory and antiviral properties of novel drug candidate ABX464 are mediated by modulation of RNA splicing","volume":"9","author":"Vautrin","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1053\/j.gastro.2013.07.001","article-title":"MicroRNA-124 Regulates STAT3 Expression and Is Down-regulated in Colon Tissues of Pediatric Patients With Ulcerative Colitis","volume":"145","author":"Koukos","year":"2013","journal-title":"Gastroenterology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.1053\/j.gastro.2021.02.054","article-title":"Induction and Long-term Follow-up with ABX464 for Moderate-to-severe Ulcerative Colitis: Results of Phase IIa Trial","volume":"160","author":"Vermeire","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1016\/S2468-1253(22)00233-3","article-title":"ABX464 (obefazimod) for moderate-to-severe, active ulcerative colitis: A phase 2b, double-blind, randomised, placebo-controlled induction trial and 48 week, open-label extension","volume":"7","author":"Vermeire","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/S2468-1253(22)00249-7","article-title":"Induction of microRNA-124 as a novel therapeutic concept in ulcerative colitis","volume":"7","author":"Atreya","year":"2022","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Vermeire, S., Solitano, V., Peyrin-Biroulet, L., Tilg, H., Danese, S., Ehrlich, H., Scherrer, D., Gineste, P., D\u2019agay, L., and Sands, B.E. (2023). Obefazimod: A First-in-class Drug for the Treatment of Ulcerative Colitis. J. Crohn\u2019s Colitis, jjad067.","DOI":"10.1093\/ecco-jcc\/jjad067"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1007\/s40265-019-01169-y","article-title":"Innovations in Oral Therapies for Inflammatory Bowel Disease","volume":"79","author":"Ma","year":"2019","journal-title":"Drugs"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/13\/1730\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:01:58Z","timestamp":1760126518000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/13\/1730"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,27]]},"references-count":54,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["cells12131730"],"URL":"https:\/\/doi.org\/10.3390\/cells12131730","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,27]]}}}