biostudies-literatureUnknown8(4)Marcoux DRecently, our research group reported the identification of prodrug amino-alcohol <b>2</b> as a potent and efficacious S1P₁ receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya <b>1</b>), whose active phosphate metabolite is an S1P₁ full agonist, in terms of pulmonary and cardiovascular safety. S1P₁ partial agonist <b>2</b>, however, has a long half-life in rodents and was projected to have a long half-life in humans. The purpose of this communication is to disclose highly potent partial agonists of S1P₁ with shorter half-lives relative to the clinical compound <b>2</b>. PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.MedChemComm725-729https://www.ebi.ac.uk/biostudies/studies/S-EPMC6071880biostudies-literatureIdentification of potent tricyclic prodrug S1P₁ receptor modulators.PMC6071880Marcoux DTaylor TLLevesque PCXiao HYMurali Dhar TGMcIntyre KWShen DRWu DRGupta ACvijic MECornelius GThomas RPragalathan BXie JHeimrich EMSun HZhou XDD'Arienzo CJSalter-Cid LLombardo LJRampulla RYang XYang ZLehman-McKeeman LDMarino AMCarter PHShi HDabros MMathur ADyckman AJfalseIdentification of potent tricyclic prodrug S1P₁ receptor modulators.Recently, our research group reported the identification of prodrug amino-alcohol <b>2</b> as a potent and efficacious S1P₁ receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya <b>1</b>), whose active phosphate metabolite is an S1P₁ full agonist, in terms of pulmonary and cardiovascular safety. S1P₁ partial agonist <b>2</b>, however, has a long half-life in rodents and was projected to have a long half-life in humans. The purpose of this communication is to disclose highly potent partial agonists of S1P₁ with shorter half-lives relative to the clinical compound <b>2</b>. PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.2017-01-01T00:00:00Z2017 Apr2025-04-19T20:59:40.523Z2019-03-26T23:51:29ZS-EPMC60718803010879110.1039/c6md00539j