Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders

Jeffrey T. Bagdanoff, Michael S. Donoviel, Amr Nouraldeen, James Tarver, Qinghong Fu, Marianne Carlsen, Theodore C. Jessop, Haiming Zhang, Jill Hazelwood, Huy Nguyen, Simon D.P. Baugh, Michael Gardyan, Kristen M. Terranova, Joseph Barbosa, Jack Yan, Mark Bednarz, Suman Layek, Lawrence F. Courtney, Jerry Taylor, Ann Marie Digeorge-FousheeSuma Gopinathan, Debra Bruce, Traci Smith, Liam Moran, Emily O'Neill, Jeff Kramer, Zhong Lai, S. David Kimball, Qingyun Liu, Weimei Sun, Sean Yu, Jonathan Swaffield, Alan Wilson, Alan Main, Kenneth G. Carson, Tamas Oravecz, David J. Augeri

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.

Original languageEnglish (US)
Pages (from-to)3941-3953
Number of pages13
JournalJournal of medicinal chemistry
Volume52
Issue number13
DOIs
StatePublished - Jul 9 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Bagdanoff, J. T., Donoviel, M. S., Nouraldeen, A., Tarver, J., Fu, Q., Carlsen, M., Jessop, T. C., Zhang, H., Hazelwood, J., Nguyen, H., Baugh, S. D. P., Gardyan, M., Terranova, K. M., Barbosa, J., Yan, J., Bednarz, M., Layek, S., Courtney, L. F., Taylor, J., ... Augeri, D. J. (2009). Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders. Journal of medicinal chemistry, 52(13), 3941-3953. https://doi.org/10.1021/jm900278w