Discovery of heterocyclic sulfonamides as sphingosine 1-phosphate receptor 1 (S1P1) antagonists. Issue 10 (15th May 2015)

• Record Type: Journal Article
• Authors: Hennessy, Edward J.; Grewal, Gurmit; Byth, Kate; Kamhi, Victor M.; Li, Danyang; Lyne, Paul; Oza, Vibha; Ronco, Lucienne; Rooney, Michael T.; Saeh, Jamal C.; Su, Qibin
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 10(2015)
• Page Start: 2041
• Page End: 2045
• Publication Date: 2015-05-15
• Subjects: Sphingosine 1-phosphate receptor 1 -- S1P1 antagonist -- Heterocyclic sulfonamide -- Lipophilic ligand efficiency; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.03.095
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: We have discovered a novel class of heterocyclic sulfonamides that act as antagonists of the S1P1 receptor. While members of this series identified from a high-throughput screen showed promising levels of potency in a cell-based assay measuring the inhibition of receptor internalization, most compounds were excessively lipophilic and contained an oxidation-prone thioether moiety. As a result, such compounds suffered from poor physical properties and metabolic stability, limiting their utility as in vivo probes. By removing the thioether group and systematically developing an understanding of structure–activity relationships and the effects of lipophilicity on potency within this series, we have been able to identify potent compounds with vastly improved physical properties. A representative enantiopure triazole sulfonamide (33 ) has measurable bioavailability following a low (3 mg/kg) oral dose in rat, highlighting an achievement of the early hit-to-lead efforts for this series.