Synthesis of benzimidazole based analogues of sphingosine-1-phosphate: discovery of potent, subtype-selective S1P4 receptor agonists

Bioorganic & Medicinal Chemistry Letters
Jeremy J ClemensTimothy L Macdonald

Abstract

Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid with the capacity to induce a broad range of cellular responses via its interaction with the S1P family of G-protein coupled receptors. A member of this receptor family, S1P(4), is highly and almost exclusively expressed in the lymphoid system and has been implicated in regulation of cell shape and motility. This report describes the synthesis of several potent benzimidazole based S1P(4) receptor selective agonists. For instance, compound 9b displayed an EC(50)=36 nM at the S1P(4) receptor using a [gamma-(35)S]GTP binding assay as compared to an EC(50)=37 nM for the endogenous ligand. We also report the effects of altering stereochemistry at the C2 position, methylation at the C1 and C2 position, and activity differences between the alcohol and phosphate head groups of the analogues.

References

Jul 24, 2003·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Takayuki KohnoYasuyuki Igarashi

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Citations

Jun 15, 2013·Trends in Pharmacological Sciences·Catherine O'Sullivan, Kumlesh K Dev
Aug 21, 2013·Nature Reviews. Drug Discovery·Gregory T KunkelSarah Spiegel
Apr 26, 2011·Trends in Molecular Medicine·Susan Pyne, Nigel J Pyne
Jan 1, 2008·Journal of Molecular Graphics & Modelling·Truc-Chi T PhamAbby L Parrill
Aug 16, 2011·British Journal of Pharmacology·Tetsuji MutohJerold Chun
Aug 3, 2016·Medicinal Research Reviews·Dominik Vogt, Holger Stark
Oct 3, 2020·International Journal of Molecular Sciences·Eileen M McGowanYiguang Lin
Nov 29, 2011·Bioorganic & Medicinal Chemistry Letters·Xinhua HeSong Li

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