page_title: Sphingosine-1-phosphate receptor modulator
section_title: Development
hierarchical_section_title: Sphingosine-1-phosphate receptor modulator / History and development / Development
caption_attribution_description: English: Modifications to ISP-1 marked with color
context_page_description: Sphingosine-1-phosphate receptor modulators are a class of drugs used as immunomodulators, most notably in cases of multiple sclerosis.
  These drugs have the ability to modulate the G-protein coupled S1P receptors. Drugs that modulate S1P1 receptors bind to those receptors in lymph nodes and prevent certain lymphoid immune cells from being excreted into the blood and reaching the central nervous system, leading to lymphopenia.
context_section_description: Researchers figured out that the metabolite ISP-1, myriocin, was 10 times more active than cyclosporin A. The first drug FTY720 (fingolimod) was developed from ISP-1. Because the metabolite itself is an amphiphilic compound and, which represent poor cellular permeability and oral bioavailability FTY720, fingolimod, was synthesized to improve these properties in vivo.
  To enhance its activity a few changes were made to the structure shown in illustration 1. In order to find an active pharmacophore the structure was simplified by removing chirality and functionality. The first chiral group, marked red on illustration 1, was removed by the conversion of the carboxyl acid to 2-amino-1,2-propane diol.
  As research continued it was discovered that reduction of the ketone and olefin groups, marked purple on illustration 1,  was tolerated. Furthermore, the remaining 3-hydroxyl and 4-hydroxyl groups marked green on illustration 1 were non-essential to its activity. They were therefore removed from the compound resulting in an achiral intermediate and daughter compound. These changes of ISP-1 resulted in continued improvements in the profile of the compound.
  To further improve the activity and safety the side chain was shortened from 28 carbons to 14 carbons marked orange on illustration 1.
  To find the lead optimization a part of the fatty acid side chain was replaced with 1,4-disubstituted phenyl ring. This was done to decrease the bond rotation. The phenyl ring was moved along the side chain to find its optimal position. These efforts resulted in the two carbon linkers from the polar head group to the phenyl moiety. The resulting product was FTY720 as shown in illustration 2 and its activated, phosphorylated form in illustrations 3a and 3b. Research showed that FTY720 had the same efficacy as ISP-1 in vitro. Moreover, it was found that FTY720 is 100 times more efficient than Cyclosporin A against experimental autoimmune encephalomyelitis (EAE) in an animal model of multiple sclerosis.
caption: Illustration 1: The parent compound ISP-1 (myriocin). The coloured groups represent the structural changes that were made to the compound to synthesize fingolimod.
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