An update on sphingosine-1-phosphate receptor 1 modulators

Abstract

Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P₁) to express a variety of symptoms and disease patterns. Inspired by its natural substrate, an array of artificial sphingolipid derivatives has been developed to target this specific G protein-coupled receptor (GPCR) in an attempt to suppress autoimmune disorders. FTY720, also known as fingolimod, is the first oral disease-modifying therapy for MS on the market. In pursuit of improved stability, bioavailability, and efficiency, structural analogues of this initial prodrug have emerged over time. This review covers a brief introduction to the sphingolipid metabolism, the mechanism of action on S1P₁, and an updated overview of synthetic sphingosine S1P₁ agonists.

Keywords: Autoimmune modulators; S1P(1) agonists; Sphingolipids; Sphingosine-1-phosphate; Sphingosine-1-phosphate receptor 1.

Figure 1.

D-threo-PDMP (a) and L-threo-PDMP (b).

Figure 2.

Metabolite RP-101075 of ozanimod.

Scheme 1.

Sphingolipid metabolism. Sphingolipid de novo biosynthesis begins with L-serine and palmitoyl-CoA being condensed to 3-ketosphinganine by 3-ketosphinganine synthase. 3-Ketosphinganine is then reduced by 3-ketosphinganine reductase and NADPH to sphinganine. N-Acylation of sphinganine through CoA-sphinganine acyl transferase with palmitic acid produces dihydroceramide which is then oxidized in its C4 position to ceramide by N-acyl sphinganine dehydrogenase in the presence of FAD. Ceramide serves as the basis for either sphingomyelin production by CMP-phosphorylcholine transferase or ganglioside biosynthesis through glycosylation with various sugars at the C1 hydroxyl position. Deacylation by ceramidase forms sphingosine, which can be converted back to ceramide when N-acylated with palmitic acid. Phosphorylation of sphingosine by sphingosine kinases 1 and 2 gives S1P, which can be also dephosphorylated by respective S1P phosphatases 1 and 2. Irreversible degradation of sphingolipids occurs through the breakdown of S1P by S1P lyase into phosphoethanolamine and hexadecenal. Hexadecenal is converted by fatty aldehyde dehydrogenase ALDH3A2 into hexadecenoate which in turn is a substrate for palmitoyl-CoA.^,,–