These modulators have gained significant attention due to their ability to alter lymphocyte trafficking and potentially provide therapeutic benefits in autoimmune diseases, particularly multiple sclerosis (MS).

[1] The most well-known compound in this class is fingolimod (FTY720), which was the first oral disease-modifying therapy approved for the treatment of relapsing-remitting MS.

The drug was developed following observations of immunosuppressive action in ISP-1 (myriocin), a natural product derived from the fungus Isaria sinclairii.

[4] The lymphopenia causing mechanism of fingolimod was discovered in 2002 and was found to be due to the drug's ability to alter the S1P1 receptor in the secondary lymphs.

Even though it has the drawback of not being a selective receptor modulator it has passed all clinical drug trials and was approved for the market in USA in 2010.

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.

[8] To find the lead optimization a part of the fatty acid side chain was replaced with 1,4-disubstituted phenyl ring.

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.

[3] The binding to receptor S1P1 is the one that contributes to the mechanism of action,[7] while the others are thought to produce the unwanted side effects of the drugs.

[3] Adverse side effect of the drugs at first dose can be bradycardia, influenza, back pain, hypertension, headache, cough, dyspnea and diarrhea.

[11] Multiple sclerosis is an autoimmune disease where immune cells attack the neurons of the central nervous system and degrade the myelin that protect them.