title: Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery.
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 molecularin vitrostudies andin vivostudies 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.
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA) and College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention (MRCA) and College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea.
authors.forename: Dong-Soon
authors.initials: DS
authors.lastname: Im
keywords: Drug discovery; FTY720; Fingolimod; G protein-coupled receptor; S1P agonist; Sphingosine 1-phosphate