2. Academic Validation
  3. Discovery and Structure-Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P1)

Discovery and Structure-Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P1)

  • J Med Chem. 2016 Jul 14;59(13):6248-64. doi: 10.1021/acs.jmedchem.6b00373.
John L Gilmore 1,  James E Sheppeck 2nd 1,  Scott H Watterson 1,  Lauren Haque 1,  Parag Mukhopadhyay 1,  Andrew J Tebben 1,  Michael A Galella 1,  Ding Ren Shen 1,  Melissa Yarde 1,  Mary Ellen Cvijic 1,  Virna Borowski 1,  Kathleen Gillooly 1,  Tracy Taylor 1,  Kim W McIntyre 1,  Bethanne Warrack 1,  Paul C Levesque 1,  Julia P Li 1,  Georgia Cornelius 1,  Celia D'Arienzo 1,  Anthony Marino 1,  Praveen Balimane 1,  Luisa Salter-Cid 1,  Joel C Barrish 1,  William J Pitts 1,  Percy H Carter 1,  Jenny Xie 1,  Alaric J Dyckman 1
Affiliations

Affiliation

  • 1 Research and Development, Bristol-Myers Squibb , P.O. Box 4000, Princeton, New Jersey 08543, United States.
PMID: 27309907 DOI: 10.1021/acs.jmedchem.6b00373
Abstract

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates a multitude of physiological processes such as lymphocyte trafficking, cardiac function, vascular development, and inflammation. Because of the ability of S1P1 receptor agonists to suppress lymphocyte egress, they have great potential as therapeutic agents in a variety of autoimmune diseases. In this article, the discovery of selective, direct acting S1P1 agonists utilizing an ethanolamine scaffold containing a terminal carboxylic acid is described. Potent S1P1 agonists such as compounds 18a and 19a which have greater than 1000-fold selectivity over S1P3 are described. These compounds efficiently reduce blood lymphocyte counts in rats through 24 h after single doses of 1 and 0.3 mpk, respectively. Pharmacodynamic properties of both compounds are discussed. Compound 19a was further studied in two preclinical models of disease, exhibiting good efficacy in both the rat Adjuvant arthritis model (AA) and the mouse experimental autoimmune encephalomyelitis model (EAE).

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