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Issue 4, 2017
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Identification of potent tricyclic prodrug S1P1 receptor modulators

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Recently, our research group reported the identification of prodrug amino-alcohol 2 as a potent and efficacious S1P1 receptor modulator. This molecule is differentiated preclinically over the marketed drug fingolimod (Gilenya 1), whose active phosphate metabolite is an S1P1 full agonist, in terms of pulmonary and cardiovascular safety. S1P1 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 S1P1 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.

Graphical abstract: Identification of potent tricyclic prodrug S1P1 receptor modulators

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The article was received on 26 Sep 2016, accepted on 21 Nov 2016 and first published on 25 Nov 2016

Article type: Research Article
DOI: 10.1039/C6MD00539J
Med. Chem. Commun., 2017,8, 725-729

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    Identification of potent tricyclic prodrug S1P1 receptor modulators

    D. Marcoux, H. Xiao, T. G. Murali Dhar, J. Xie, L. D. Lehman-McKeeman, D. Wu, M. Dabros, X. Yang, T. L. Taylor, X. D. Zhou, E. M. Heimrich, R. Thomas, K. W. McIntyre, H. Shi, P. C. Levesque, H. Sun, Z. Yang, A. M. Marino, G. Cornelius, C. J. D'Arienzo, A. Gupta, B. Pragalathan, R. Rampulla, A. Mathur, D. R. Shen, M. E. Cvijic, L. Salter-Cid, L. J. Lombardo, P. H. Carter and A. J. Dyckman, Med. Chem. Commun., 2017, 8, 725
    DOI: 10.1039/C6MD00539J

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