{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T17:15:07Z","timestamp":1765041307244,"version":"3.41.2"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T00:00:00Z","timestamp":1661126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020430","name":"LG Chem","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020430","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Aim:<\/jats:bold> Sphingosine-1-phosphate receptor mediates the egress of lymphocytes from lymphoid organs, and its inhibition results in a decreased number of circulating lymphocytes. The aim of the current study was to investigate the safety and pharmacodynamic and pharmacokinetic characteristics of a novel sphingosine-1-phosphate receptor modulator, LC51-0255.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> A phase 1 randomized, double-blind, placebo-controlled, multiple dosing, dose-escalation study was conducted on healthy Korean male subjects.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> After single and daily administration of LC51-0255 for 21 days, a dose-dependent decrease in lymphocyte count and heart rate was observed through 0.25\u20132\u00a0mg dose range of LC51-0255. The mean elimination half-life of LC51-0255 was 76\u201395\u00a0h. LC51-0255 was accumulated with a mean accumulation ratio of 5.17\u20136.64. During the study, LC51-0255 was generally well tolerated. The most common treatment-emergent adverse event was bradycardia. No clinically significant event of arrhythmia, including AV block, was observed. No clinically significant difference in blood pressure was observed between the dose groups. In other safety assessments, no clinically significant abnormalities were observed, except for bradycardia.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Daily administration of LC51-0255 in the range of 0.25\u20132\u00a0mg resulted in a dose-dependent reduction of lymphocyte counts and heart rate. LC51-0255 is generally safe and well tolerated in healthy volunteers.<\/jats:p>","DOI":"10.3389\/fphar.2022.930615","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T09:13:22Z","timestamp":1661159602000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Dose-dependent reduction of lymphocyte count and heart rate after multiple administration of LC51-0255, a novel sphingosine-1-phosphate receptor 1 modulator, in healthy subjects"],"prefix":"10.3389","volume":"13","author":[{"given":"Inyoung","family":"Hwang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang Won","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaeseong","family":"Oh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SeungHwan","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In-Jin","family":"Jang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyung-Sang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1007\/s40265-019-01140-x","article-title":"Siponimod: First global approval","volume":"79","author":"Al-salama","year":"2019","journal-title":"Drugs"},{"key":"B2","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.tem.2007.07.005","article-title":"Autocrine and paracrine roles of sphingosine-1-phosphate","volume":"18","author":"Alvarez","year":"2007","journal-title":"Trends Endocrinol. Metab."},{"key":"B3","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1016\/j.ahj.2014.06.028","article-title":"Cardiac and vascular effects of fingolimod: Mechanistic basis and clinical implications","volume":"168","author":"Camm","year":"2014","journal-title":"Am. Heart J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1007\/s40265-020-01431-8","article-title":"Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: Differential downstream receptor signalling and clinical profile effects","volume":"81","author":"Chun","year":"2021","journal-title":"Drugs"},{"key":"B5","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1146\/annurev.immunol.23.021704.115628","article-title":"Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs","volume":"23","author":"Cyster","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1080\/00498254.2017.1329568","article-title":"Ponesimod, a selective sphingosine 1-phosphate (S1P1) receptor modulator for autoimmune diseases: Review of clinical pharmacokinetics and drug disposition","volume":"48","author":"Dash","year":"2018","journal-title":"Xenobiotica."},{"key":"B7","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/j.msard.2014.05.005","article-title":"First-dose effect of fingolimod: Pooled safety data from two phase 3 studies (TRANSFORMS and FREEDOMS)(P830)","volume":"3","author":"Dimarco","year":"2010","journal-title":"Mult. Scler."},{"key":"B8","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1177\/1352458513500551","article-title":"Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy","volume":"20","author":"Francis","year":"2014","journal-title":"Mult. Scler."},{"key":"B9","doi-asserted-by":"publisher","first-page":"109","DOI":"10.12703\/P6-109","article-title":"S1P signaling: New therapies and opportunities","volume":"6","author":"Gonzalez-Cabrera","year":"2014","journal-title":"F1000Prime Rep."},{"key":"B10","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.1212\/WNL.0b013e3182735d24","article-title":"Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod","volume":"79","author":"Gross","year":"2012","journal-title":"Neurology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1080\/17425255.2016.1196188","article-title":"Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators","volume":"12","author":"Juif","year":"2016","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"article-title":"Nonclinical safety assessment of LC51-0255, an oral sphingosine-1-phosphate 1 receptor (S1P1) modulator with a favorable profile","year":"2019","author":"Kim","key":"B12"},{"key":"B13","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1177\/0091270004264165","article-title":"Multiple-dose FTY720: Tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects","volume":"44","author":"Kovarik","year":"2004","journal-title":"J. Clin. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"98","DOI":"10.5414\/cpp45098","article-title":"Ethnic sensitivity study of fingolimod in white and Asian subjects","volume":"45","author":"Kovarik","year":"2007","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"B15","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1007\/s40265-020-01319-7","article-title":"Ozanimod: First approval","volume":"80","author":"Lamb","year":"2020","journal-title":"Drugs"},{"key":"B16","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/nature02284","article-title":"Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1","volume":"427","author":"Matloubian","year":"2004","journal-title":"Nature"},{"key":"B17","doi-asserted-by":"publisher","first-page":"80","DOI":"10.4062\/biomolther.2016.160","article-title":"Sphingosine 1-phosphate receptor modulators and drug discovery","volume":"25","author":"Park","year":"2017","journal-title":"Biomol. Ther."},{"key":"B18","doi-asserted-by":"publisher","first-page":"2002","DOI":"10.1212\/WNL.0b013e3182735d00","article-title":"Varicella-zoster virus encephalitis and vasculopathy in a patient treated with fingolimod","volume":"79","author":"Ratchford","year":"2012","journal-title":"Neurology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1177\/2050640615576676","article-title":"The genetic epidemiology of diverticulosis and diverticular disease: Emerging evidence","volume":"3","author":"Reichert","year":"2015","journal-title":"United Eur. Gastroenterol. J."},{"key":"B20","doi-asserted-by":"publisher","first-page":"354","DOI":"10.5114\/ceji.2015.54599","article-title":"Influence of fingolimod on basic lymphocyte subsets frequencies in the peripheral blood of multiple sclerosis patients - preliminary study","volume":"40","author":"Rudnicka","year":"2015","journal-title":"Cent. Eur. J. Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"6463","DOI":"10.3390\/ijms21186463","article-title":"Morpholino analogues of fingolimod as novel and selective S1P1 ligands with in vivo efficacy in a mouse model of experimental antigen-induced encephalomyelitis","volume":"21","author":"Stepanovska","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1212\/WNL.0b013e31821043b5","article-title":"Primary varicella zoster infection associated with fingolimod treatment","volume":"76","author":"Uccelli","year":"2011","journal-title":"Neurology"},{"key":"B23","unstructured":"(Pre-clinical trial) Development of novel oral agents for multiple sclerosis2014"},{"key":"B24","first-page":"037","article-title":"Fingolimod therapy for multiple sclerosis","volume-title":"Seminars in neurology","author":"Willis","year":"2013"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1111\/cts.13227","article-title":"Single-dose of LC51-0255, a selective S1P(1) receptor modulator, showed dose-dependent and reversible reduction of absolute lymphocyte count in humans","volume":"15","author":"Lee","year":"2022","journal-title":"Clin. Transl. Sci."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.930615\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T09:13:25Z","timestamp":1661159605000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.930615\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,22]]},"references-count":25,"alternative-id":["10.3389\/fphar.2022.930615"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.930615","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2022,8,22]]},"article-number":"930615"}}