sphingosine 1-phosphate receptor 1 as a useful target for treatment of multiple sclerosis鞘氨醇1-phosphate受体1作为一个有用的治疗多发性硬化症的目标.pdf

Pharmaceuticals 2012, 5, 514-528; doi:10.3390/ph5050514 OPEN ACCESS Pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis Kenji Chiba * and Kunitomo Adachi Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan; E-Mail: Adachi.Kunitomo@mc.mt-pharma.co.jp (K.A.) * Author to whom correspondence should be addressed; E-Mail: Chiba.Kenji@mk.mt-pharma.co.jp; Tel.: +81-45-963-4342; Fax: +81-45-963-7316. Received: 5 April 2012; in revised form: 24 April 2012 / Accepted: 15 May 2012 / Published: 18 May 2012 Abstract: Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P ) plays an essential role in lymphocyte egress from secondary lymphoid 1 organs (SLO), as evinced by the inability of lymphocytes to exit from the SLO in mice lacking lymphocytic S1P . Fingolimod hydrochloride (FTY720) is a first-in-class, orally 1 active, S1P receptor modulator with a structure closely related to sphingosine. FTY720 was first synthesized by chemical modification of a natural product, myriocin. FTY720 is effectively converted to an active metabolite, FTY720 phosphate (FTY720-P) by sphingosine ki