Sphingosine 1-phosphate (S1P) mediates a variety of biological functions through five G-protein coupled receptors S1P1-S1P5.  The development of FTY720 (fingolimod), a pan-antagonist at S1P1, S1P3, S1P4, and S1P5, as immunosuppressant has stimulated extensive interest in searching for S1P receptor modulators, particularly receptor sub-type selective agents for a broad range of therapeutic applications.  Like S1P1 and S1P2, S1P3 is widely expressed, although its genetic deletion has no obvious phenotypes.  Studies have suggested that S1P3 agonism is responsible for the transient bradycardia of FTY720 in humans and rodents.  In addition, there is increasing evidence that implicates the role of S1P3 in vascular permeability, inflammation, myofibroblast differentiation, and vasorelaxation.  We herein describe the synthesis and structure-activity relationship of a novel series of indole-3-carboxylamides as S1P3 selective antagonists with nanomolar potency, which are useful in further understanding the pharmacology of S1P3 and its potential as a therapeutic target.

Discovery, optimization, and structure-activity relationship of a novel series of indole-3-carboxylamide S1P<sub>3</sub> selective antagonists

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

Discovery, optimization, and structure-activity relationship of a novel series of indole-3-carboxylamide S1P3 selective antagonists

Discovery, optimization, and structure-activity relationship of a novel series of indole-3-carboxylamide S1P₃ selective antagonists