{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T03:00:50Z","timestamp":1760151650530,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,17]],"date-time":"2022-04-17T00:00:00Z","timestamp":1650153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1R01AI105836-01A1"],"award-info":[{"award-number":["1R01AI105836-01A1"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A growing body of evidence suggests a pathogenic role for pro-inflammatory T helper 17 cells (Th17) in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type I diabetes, and psoriasis\u2014diseases for which no curative treatment is currently available. The nuclear retinoic acid receptor\u2013related orphan receptors alpha and gamma (ROR\u03b1\/\u03b3), in particular the truncated isoform ROR\u03b3t that is specifically expressed in the thymus, play a critical role in the activation of a pro-inflammatory Th17 response, and ROR\u03b3 inverse agonists have shown promise as negative regulators of Th17 for the treatment of autoimmune diseases. Our study underscores the screening of a large combinatorial library of 1,5-disubstituted acylated 2-amino-4,5-dihydroimidazoles using a demonstrated synthetic and screening approach and the utility of the positional scanning libraries strategy for the rapid identification of a novel class of ROR inhibitors. We identified compound 1295-273 with the highest activity against ROR\u03b3 (3.3 \u00b5M IC50) in this series, and almost a two-fold selectivity towards this receptor isoform, with 5.3 and 5.8 \u00b5M IC50 against ROR\u03b1 and ROR\u03b2 cells, respectively.<\/jats:p>","DOI":"10.3390\/ijms23084433","type":"journal-article","created":{"date-parts":[[2022,4,18]],"date-time":"2022-04-18T04:21:28Z","timestamp":1650255688000},"page":"4433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["1,5-Disubstituted Acylated 2-Amino-4,5-dihydroimidazoles as a New Class of Retinoic Acid Receptor\u2013Related Orphan Receptor (ROR) Inhibitors"],"prefix":"10.3390","volume":"23","author":[{"given":"Maria A.","family":"Ortiz","sequence":"first","affiliation":[{"name":"Donald P. Shiley BioScience Center, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F. Javier","family":"Piedrafita","sequence":"additional","affiliation":[{"name":"Donald P. Shiley BioScience Center, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adel","family":"Nefzi","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port Saint Lucie, FL 34987, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/0092-8674(95)90199-X","article-title":"The nuclear receptor superfamily: The second decade","volume":"83","author":"Mangelsdorf","year":"1995","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.chembiol.2011.12.011","article-title":"Targeting orphan nuclear receptors for treatment of metabolic diseases and autoimmunity","volume":"19","author":"Burris","year":"2012","journal-title":"Chem. 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