Fty720 Fingolimod

Structural Formula Ball-and-Stick Model Space-filling Model

Year of discovery: 1995 (Yoshitomi); Drug category: Immunosuppressant; Main uses: Clinical trials have shown positive signs of benefit for the autoimmune disease multiple sclerosis.

FTY720, also known as fingolimod, was first synthesized at Yoshitomi Pharmaceuticals in Japan in 1995 as a synthetic analog of ISP-1 (myriocin, thermozymocidin), a compound that was isolated from a fungus in a search for novel anticancer agents. ISP-1 did not have antitumor activity, but surprisingly it was a potent immunosuppressant, although too toxic for further development. Extensive studies of ISP-1 derivatives led to simple synthetic analogs that retain the immunosuppressive activity.

OH OH

OH OH

The potent immunosuppressive activity and the simple and unique structure of FTY720 came to the attention of scientists at Sandoz (later Novartis), and after investigation of its immunosuppressive properties they purchased commercial rights to the drug.1

Early studies revealed that FTY720 exerts its biological effect in a significantly different way from the other known immunosuppressants. Whereas earlier drugs such as cyclosporin (see page 124) and tacrolimus (see page 125) block the activation of B- and T-lymphocytes, FTY720 localizes B- and T-lymphocytes in the lymph nodes, thereby preventing attack on implanted grafts by T-cells. Although B-lymphocytes are retained in the nodes, those B-cells that recognize the circulating virus release an antibody specific for that virus into the circulation and periphery. Bacteria are attacked in the same way. Consequently, the use of FTY720 causes more discriminating and less inflammatory immunosuppression than the older drugs.

The localization of lymphocytes in the lymph nodes is thought to result because FTY720 resembles sphingosine, a natural lipid molecule that participates in protein signaling.

Nh2 Sphingosine

Workers at Sandoz in collaboration with K. Lynch at the University of Virginia discovered that a phosphorylated derivative of FTY720 (FTY720-P) forms in the body and acts on sphingosine-1-phosphate (S1P) receptors. The role of these receptors in immune cell trafficking was elucidated by immunologist J. Cyster at the University of California, San Francisco. A subtype of these receptors, S1P-1 is present in large amounts on lymphocytes. When lymphocytes return to the lymph nodes to multiply, the level of these receptors on the cell membrane is reduced. When they are ready to exit, the level is increased, sensitizing them to S1P molecules and provoking the migration of these cells from the nodes to the circulation. FTY720-P strongly activates the S1P-1 receptors, which, in response, pull back inside the cell; thus, the cell is unable to leave the lymph node.2

Clinical studies have shown FTY720 to be a promising treatment for multiple sclerosis, an autoimmune disorder affecting the nervous system. In multiple sclerosis, myelin, a fatty layer that insulates nerve fibers and allows conduction of electrical signals (see page 221), is attacked and disintegrated by the immune system.

FTY720 may cause a substantial lowering of heart rate (bradycardia), a side effect which demands termination of the treatment.

1. Transplant Proc. 2004. 36, 531S-543S; 2. Transplant. Proc. 1999, 31, 2779-2782; Refs. p. 174

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