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

• Published in: Journal of antibiotics 2020-10, Vol.73 (10), p.666-678
• Main Author: Chiba, Kenji
• Format: Article
• Language: English
• Subjects: 13; 13/21; 13/31; 631/250/1619/554; 631/250/38; Amino acids; Animals; Bacteriology; Biomedical and Life Sciences; Bioorganic Chemistry; Central nervous system; Drug Discovery; Fatty Acids, Monounsaturated - chemistry; Fatty Acids, Monounsaturated - isolation & purification; Fingolimod Hydrochloride - chemical synthesis; Fingolimod Hydrochloride - pharmacology; Fingolimod Hydrochloride - therapeutic use; Humans; Hypocreales - chemistry; Life Sciences; Lymphocytes; Lymphocytes - drug effects; Medicinal Chemistry; Microbiology; Multiple Sclerosis - drug therapy; Natural products; Organic Chemistry; Special Feature: Review Article; Structure-Activity Relationship
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/s41429-020-0351-0

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 (S1P 1 ) plays an essential role in lymphocyte circulation and that the molecular target of fingolimod is S1P 1 . Phosphorylated fingolimod acts as a “functional” antagonist at S1P 1 , modulates lymphocyte circulation, and shows a potent immunosuppressive activity. Fingolimod significantly reduced the relapse rate of MS in the clinical studies and has been approved as a new therapeutic drug for MS in more than 80 countries.