FTY720 Story: Discovery of the First Sphingosine 1-Phosphate Receptor Modulator

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  • Adachi Kunitomo
    Mitsubishi Tanabe Pharma Corporation, Research Division, Medicinal Chemistry Research Laboratories I

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Other Title
  • ＦＴＹ７２０創薬物語：世界初のスフィンゴシン１‐リン酸受容体調節薬の創製
  • FTY720創薬物語:世界初のスフィンゴシン 1-リン酸受容体調節薬の創製
  • FTY720ソウヤクモノガタリ セカイ ハツ ノ スフィンゴシン 1 リンサン ジュヨウタイ チョウセツヤク ノ ソウセイ

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Description

FTY720 (Fingolimod) is the first of a novel class: Sphingosine 1-phosphate (S1P) receptor modulator and has been approved in the US, Russia, Switzerland, Australia and EU as a first-line treatment for relapsing forms of multiple sclerosis (MS) so far. FTY720 was designed and synthesized 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. ISP-I is an amino acid having three successive asymmetric centers and some functionalities. We simplified the structure drastically to find a symmetric 2-substitued-2-aminopropane-1,3-diol framework for an in vivo immunosuppressive activity and finally discovered FTY720. During the lead optimization, we encountered an unexpected dramatic change of the mechanism. FTY720 is mainly phosphorylated by sphingosine kinease 2 in vivo and the phosphorylated drug (FTY720-P) acts as a potent agonist of four of the five G protein coupled receptors for S1P: S1P1, S1P3, S1P4, and S1P5. Immunomodulation by FTY720-P is based on agonism at the S1P1 receptor. FTY720 was discovered by a classical “physiology-based drug discovery” strategy, showing that such a strategy as adopted by the FTY720 program would more likely meet serendipity compared to the recent strategies such as “target-based drug discovery”.

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