Discovery of fingolimod based on the chemical modification of a natural product from the fungus, Isaria sinclairii.

The Journal of Antibiotics
Kenji Chiba

Abstract

Fingolimod is a first-in-class of sphingosine-1-phosphate (S1P) receptor modulator and is widely used a therapeutic drug for multiple sclerosis (MS), autoimmune disease in the central nervous system. About 25 year ago, a natural product, myriocin was isolated from culture broths of the fungus Isaria sinclairii. Myriocin, a rather complex amino acid having three successive asymmetric centers, was found to show a potent immunosuppressive activity in vitro; however, it induced a strong toxicity in vivo. To find out a less toxic immunosuppressive candidate, the chemical structure of myriocin was simplified to a nonchiral symmetric 2-substituted-2-aminoproane-1,3-diol framework. Finally, a highly potent immunosuppressant, fingolimod was found by the extensive chemical modification and pharmacological evaluation using skin allograft model in vivo. Throughout the analyses of the mechanism action of fingolimod, it is revealed that S1P receptor 1 (S1P1) plays an essential role in lymphocyte circulation and that the molecular target of fingolimod is S1P1. Phosphorylated fingolimod acts as a "functional" antagonist at S1P1, modulates lymphocyte circulation, and shows a potent immunosuppressive activity. Fingolimod significantly reduced th...Continue Reading

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Methods Mentioned

BETA
chemical modification
chemical modifications

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