Identification of potent tricyclic prodrug S1P1 receptor modulators† †The authors declare no competing interests. ‡ ‡Electronic supplementary information (ESI) available: Biology and chemistry protocols. See DOI: 10.1039/c6md00539j

• Published in: MedChemComm 2016-11, Vol.8 (4), p.725-729
• Main Authors: Marcoux, David, Xiao, Hai-Yun, Murali Dhar, T. G., Xie, Jenny, Lehman-McKeeman, Lois D., Wu, Dauh-Rurng, Dabros, Marta, Yang, Xiaoxia, Taylor, Tracy L., Zhou, Xia D., Heimrich, Elizabeth M., Thomas, Rochelle, McIntyre, Kim W., Shi, Hong, Levesque, Paul C., Sun, Huadong, Yang, Zheng, Marino, Anthony M., Cornelius, Georgia, D'Arienzo, Celia J., Gupta, Anuradha, Pragalathan, Bala, Rampulla, Richard, Mathur, Arvind, Shen, Ding Ren, Cvijic, Mary Ellen, Salter-Cid, Luisa, Lombardo, Louis J., Carter, Percy H., Dyckman, Alaric J.
• Format: Article
• Language: English
• Subjects: Chemistry
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c6md00539j

Herein, S1P 1 partial agonists with shorter half-life than our previous clinical candidate are reported. The pulmonary and cardiac safety are assessed, issues currently observed with commercial Gilenya. Recently, our research group reported the identification of prodrug amino-alcohol 2 as a potent and efficacious S1P 1 receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya 1 ), whose active phosphate metabolite is an S1P 1 full agonist, in terms of pulmonary and cardiovascular safety. S1P 1 partial agonist 2 , 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 S1P 1 with shorter half-lives relative to the clinical compound 2 . PK/PD relationships as well as their preclinical pulmonary and cardiovascular safety assessment are discussed.