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Nevertheless, the drugs for external use have not been upgraded for decades. We modified acetyl\u201011\u2010keto\u2010beta\u2010boswellic acid (ABKA), a natural compound shown to treat psoriasis animal models, to improve efficacy and solubility for topical use.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Eleven compounds were synthesized using AKBA as a lead compound, and their effects on Th17 cell differentiation were screened. 3\u2010O\u2010cyclohexanecarbonyl\u201011\u2010keto\u2010\u03b2\u2010boswellic acid (CKBA) potently inhibited Th17 cell differentiation. Its efficacy in a mouse model of psoriasis was assessed along with its pharmacology and safety profile when topically or systemically delivered to several animal species.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>CKBA inhibited mouse and human Th17 cell differentiation with an IC<jats:sub>50<\/jats:sub> of 3.28 and 3.61\u2009\u03bcM, respectively, and directly targeted acetyl\u2010CoA carboxylase 1 (ACC1). Safety evaluation and toxicity tests suggested that systemically delivered high\u2010dose CKBA for 14\u2009days had no dose\u2010associated adverse effects on the CNS, haematopoietic, cardiovascular, respiratory and digestive systems of cynomolgus monkeys. CKBA ointment permeated the skin and did not irritate or sensitize intact skin. CKBA ointment mediated dose\u2010dependent suppression of imiquimod\u2010induced psoriasis\u2010like skin inflammation with slow absorption and limited bioavailability (&lt;10% in rats and &lt;1% in minipigs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>CKBA is safe when topically or systemically delivered to animals. The beneficial effects of CKBA ointment in a mouse model of psoriasis indicate that this is a promising drug candidate for further development as a treatment for psoriasis.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16253","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T05:29:18Z","timestamp":1695706158000},"page":"1290-1307","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Identification and pre\u2010clinical investigation of 3\u2010O\u2010cyclohexanecarbonyl\u201011\u2010keto\u2010\u03b2\u2010boswellic acid as a drug for external use to treat psoriasis"],"prefix":"10.1111","volume":"181","author":[{"given":"Fangzhou","family":"Lou","sequence":"first","affiliation":[{"name":"Precision Research Center for Refractory Diseases Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyao","family":"Xu","sequence":"additional","affiliation":[{"name":"Precision Research Center for Refractory Diseases Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Bai","sequence":"additional","affiliation":[{"name":"Precision Research Center for Refractory Diseases Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing'e","family":"Zhao","sequence":"additional","affiliation":[{"name":"BCY Pharm Co., Ltd.  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Cui","sequence":"additional","affiliation":[{"name":"BCY Pharm Co., Ltd.  Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Li","sequence":"additional","affiliation":[{"name":"The Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6302-6927","authenticated-orcid":false,"given":"Honglin","family":"Wang","sequence":"additional","affiliation":[{"name":"Precision Research Center for Refractory Diseases Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,11]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15540"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15541"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15542"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.4006"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2018.12.036"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3704"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03188-w"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15868"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2015.04.039"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2020.01.015"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.07.014"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.a2813"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(07)61128-3"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/1346-8138.15727"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15178"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-020-0285-7"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.13854"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1538\/expanim.19-0128"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.5114\/ada.2020.94832"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21207488"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1468-3083.2011.04113.x"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.det.2014.09.006"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081438"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2013.477"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27180"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900521"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2011.08.003"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2020.107686"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.16253","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,18]],"date-time":"2024-03-18T04:23:29Z","timestamp":1710735809000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.16253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,11]]},"references-count":30,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1111\/bph.16253"],"URL":"https:\/\/doi.org\/10.1111\/bph.16253","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,11]]},"assertion":[{"value":"2022-08-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}