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

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

Kunitomo Adachi et al. Perspect Medicin Chem.

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: S1P(1), S1P(3), S1P(4) and S1P(5). Evidence has accumulated that immunomodulation by FTY720-P is based on agonism at the S1P(1) receptor. Medicinal chemistry targeting S1P(1) 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.

Keywords: FTY720; Fingolimod; immunomodulator; multiple sclerosis; sphingosine 1-phosphate; sphingosine 1-phosphate receptor agonist.

Figures

Figure 1.
Figure 1.
Structure of CsA, FK506, ISP-I and FTY720.
Figure 2.
Figure 2.
Optimization of the structure starting from ISP-I.
Figure 3.
Figure 3.
Role of the hydroxymethyl groups of FTY720.
Figure 4.
Figure 4.
Structures of sphingosine, S1P and (S)-FTY720-P.
Figure 5.
Figure 5.
(S)-FTY720-P inhibits S1P/S1P1-dependent lymphocyte egress from lymphoid tissues by long-term internalization and degradation of S1P1.
Figure 6.
Figure 6.
Synthetic routes for FTY720.
Figure 7.
Figure 7.
Asymmetric syntheses of FTY720-P enantiomers.
Figure 8.
Figure 8.
Agents that do not need phosphorylation by sphingosine kinase.
Figure 9.
Figure 9.
Other S1P receptor agonists/ antagonists.

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