Biomol Ther.  2017 Jan;25(1):80-90. 10.4062/biomolther.2016.160.

Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

• Park SJ
• Im DS

• KMID: 2367621
• DOI: http://doi.org/10.4062/biomolther.2016.160

Abstract

Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, S1P₁₋₅. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn's disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications.

Keyword

Sphingosine 1-phosphate; G protein-coupled receptor; Fingolimod; FTY720; Drug discovery; S1P agonist

MeSH Terms

Acute Kidney Injury
Animals
Clone Cells
Cloning, Organism
Colitis, Ulcerative
Dermatomyositis
Drug Discovery*
Fingolimod Hydrochloride
Graft Rejection
In Vitro Techniques
Liver Failure
Mice
Multiple Sclerosis
Polymyositis
Psoriasis
Receptors, Lysosphingolipid*
Second Messenger Systems
Sphingosine*
Stroke
Fingolimod Hydrochloride
Receptors, Lysosphingolipid
Sphingosine