FTY720 Story. Its Discovery and the following Accelerated Development of Sphingosine 1-Phosphate Receptor Agonists as Immunomodulators Based on Reverse Pharmacology

Abstract

Fingolimod (FTY720) is the first of a novel class: sphingosine 1-phosphate (S1P) receptor modulator and is currently in phase 3 clinical trials for multiple sclerosis (MS). FTY720 was first synthesized in 1992 by chemical modification of an immunosuppressive natural product, ISP-I (myriocin). ISP-I was isolated from the culture broth of Isaria sinclairii, a type of vegetative wasp that was an ‘eternal youth’ nostrum in traditional Chinese medicine. ISP-I is an amino acid having three successive asymmetric centers and some functionalities. We simplified the structure drastically to find a nonchiral symmetric 2-substitued-2-aminopropane-1,3-diol framework for an in vivo immunosuppressive activity (inhibition of rat skin allograft rejection test or prolonging effect on rat skin allograft survival) and finally discovered FTY720. During the course of the lead optimization process, we encountered an unexpected dramatic change of the mechanism of action with an in vivo output unchanged. Since it proved that FTY720 did not inhibit serine palmitoyltransferase that is the target enzyme of ISP-I, reverse pharmacological approaches have been preformed to elucidate that FTY720 is mainly phosphorylated by sphingosine kinease 2 in vivo and the phosphorylated drug acts as a potent agonist of four of the five G protein coupled receptors for S1P: S1P1, S1P3, S1P4 and S1P5. Evidence has accumulated that immunomodulation by FTY720-P is based on agonism at the S1P1 receptor. Medicinal chemistry targeting S1P1 receptor agonists is currently in progress. The FTY720 story provides a methodology where in vivo screens rather than in vitro screens play important roles in the lead optimization. Unlike recent drug discovery methodologies, such a strategy as adopted by the FTY720 program would more likely meet serendipity.

The Role of Sphingolipids in Arachidonic Acid Metabolism

“…FTY720 {2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol} is structurally similar to sphingosine and the lead compound from which it was derived, ISP-1 (myriocin), was isolated from the culture broth of Isaria sinclairii (25). Also known as Fingolimod, or by the trade name Gilenya TM , FTY720 is currently used clinically to quell the symptoms and slow the progression of multiple sclerosis.…”

Galactosylsphingosine (psychosine)-induced demyelination is attenuated by sphingosine 1-phosphate signalling

“…These receptors are targets for the drug pFTY720 (fingolimod), which is the first oral therapy for relapsing remitting multiple sclerosis (Kappos et al, 2010). The proposed mechanism of action for pFTY720 is reported as being dependent on internalisation of S1PRs in T cells, which limits their S1P-mediated egress from lymph nodes and thus attenuates the inflammatory response in the brains of multiple sclerosis patients (Adachi and Chiba, 2008). Importantly, a number of studies have now demonstrated that compounds such as pFTY720 can also regulate neuronal and glial cell function (Balatoni et al, 2007;Choi et al, 2011;Fischer et al, 2011;Osinde et al, 2007).…”

Targeting molecules involved in immune cell trafficking to the central nervous system for therapy in multiple sclerosis

“…Myriocin was isolated from the culture broth of a type of entomopathogenic fungus (Isaria sinclairii), which was an eternal youth nostrum in traditional medicine. 57 Showing positive results in both in vitro and in vivo screening, myriocin was modified through a series of steps to yield fingolimod, code named at the time FTY720. 58 Mechanistic analysis showed that fingolimod (FTY720) also affects lymphocyte migration, and it is the first oral therapeutic approved by the Food and Drug Administration (2010) for treatment of relapsing forms of MS at a dose of 0.5 mg given orally once a day.…”