Description
Approved by the U.S. FDA in September 2010, fingolimod (also referred
to as FTY720) is the first approved oral therapy for the relapsing-remitting
form ofmultiple sclerosis (RRMS). Because of fingolimod’s structural
resemblance to sphingosine, a metabolite of sphingolipids that constitutes
the cell membrane of all eukaryotic cells, it was hypothesized that
fingolimod may be affecting sphingolipid metabolism in cells. A series of
elegant in vitro and in vivo studies confirmed that fingolimod is
converted to (S)-fingolimod phosphate primarily by sphingosine kinase-
2 and that (S)-fingolimod phosphate mediates multiple biological processes
by binding to novel GPCR’s referred to as sphingosine-1-phosphate (S1P)
receptors. S1P receptors are divided into five subtypes, S1P1–5, which have
varying tissue and cellular distribution. S1P1–3 receptors are ubiquitously
expressed in the immune, cardiovascular, and central nervous systems, S1P4
is restricted to the hematopoietic system, and S1P5 is mostly localized in the
white matter of CNS. S1P1–3 receptors play important roles in endothelial
barrier function, maintaining vascular tone, regulating heart rate and allowing
for lymphocyte egress fromsecondary lymphoid organs. The functional
role of S1P4 is unknown,while the S1P5 receptor is thought to be involved in
natural killer cell trafficking and oligodendrocyte function.
Chemical Properties
White Solid
Originator
Yoshitomi Pharmaceutical Industries
(now Mitsubishi Tanabe Pharma) (United States)
Uses
A cell-permeable aminopropanediol immunosuppressive agent that displays lymphocyte sequestration properties.
Uses
A derivative of ISP-1 (myriocin), a fungal metabolite of the Chinese herb Iscaria sinclarii as well as a structural analogue of Sphingosine. It is a novel immune modulator that prolongs allograft transplant survival in numberour models by inhibitin
Uses
FTY720 is a derivative of ISP-1 (myriocin), a fungal metabolite of the Chinese herb Iscaria sinclarii as well as a structural analogue of Sphingosine. FTY720 is a novel immune modulator that prolong
s allograft transplant survival in numberour models by inhibiting lymphocyte emigration from lymphoid organs. FTY720 us reported to be phosphorylated by sphingosine kinase to FTY720-P, which has been
shown to potently stimulate GTPgS binding activity in S1P-transfected CHO cells (EC50 = 210 pM, 4.9 nM, 4.3 nM, and 1 nM for S1P1, S1P3, S1P4 and S1P5, respectively).
Uses
Oral medicine for the treatment of multiple sclerosis
Definition
ChEBI: The hydrochloride salt of 2-amino-2-[2-(4-octylphenyl) ethyl]-1,3-propanediol (fingolimod).
Biochem/physiol Actions
FTY720 is an immunomodulating drug and sphingosine 1-phosphate (S1P) receptor modulator. Phosphorylation of FTY270 by sphingosine kinase causes S1P1R internalization, which sequesters lymphocytes in lymph nodes, preventing them from taking part in an autoimmune response. Clinically, it has been approved for the treatment of multiple sclerosis (MS). It has also been shown to block and reverse paclitaxel-induced chemotherapy induced peripheral neuropathy (CIPN) through S1PR inhibition as well as inhibit the activity of histone deacetylases in the hippocampus of mouse brains, thereby modulating memory.
Clinical Use
Fingolimod hydrochloride is an immunosuppressive drug developed by Novartis and approved in the
U.S., Europe, and Australia in 2010 for the treatment of multiple sclerosis. The structure of
fingolimod derives from the naturally-occurring myriocin (ISP-1) metabolite of the fungus I. sinclairii
and the aminoalcohol functionality within the drug possesses structural similarity to the sphingosine
family of natural products.
Synthesis
Although several convenient preparations of fingolimod (FTY720)
have been reported in the literature, the route most closely resembling the process-scale
approach is described in the scheme. Friedel-Crafts acylation of commercial toluene derivative 89
with bromoacetyl chloride followed by ethoxide-mediated N-acylated aminomalonate (91) attack onto
the resulting -bromoketone 90 gave rise to ketoamide 92 in good overall yield. Next, separate hydride
reduction protocols were employed to furnish diol 93. Presumably, triethylsilyl hydride reduced the
ketone and both ethyl esters within 92 to the corresponding diacid, which then underwent lithium
aluminum hydride treatment to arrive at diol 93. Careful attention to stoichiometry was required to
avoid over reduction of amide 93, which was critical to achieve high-yielding (76%) salt formation of
fingolimod HCl (VI) through the use of 6 N ethanolic hydrochloric acid.
target
COX | PGE | Histamine Receptor | PAK | p21 | S1P
References
1) Brinkmann et al. (2002), The immune modulator FTY720 targets spingosine-1-phosphate receptors; J. Biol. Chem., 277 21453
2) Wolf et al. (2009), The sphingosine 1-phosphate receptor agonist FTY720 potently inhibits regulatory T cell proliferation in vitro and in vivo; J. Immunol., 183 3751
3) Awojoodu et al. (2013), Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis; Proc. Natl. Acad. Sci. USA, 110 13785
4) Chiba (2005), FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors; Pharmacol. Ther., 108 308
