s1p3

BAF312 (Siponimod (BAF-312)), a next-generation S1P receptor modulator, is specific for S1P1 and S1P5 receptors with EC50 of 0.39 nM and 0.98 nM, respectively. The specificity of BAF312 for S1P1 and S1P5 receptors exhibits >1000-fold over S1P2, S1P3 and S1P4 receptors.

CYM50260 is a potent and highly selective agonist of the sphingosine-1-phosphate 4 receptor (S1P4-R, EC50= nM), exhibiting no activity against S1P1-R, S1P2-R, S1P3-R, and S1P5-R.

TY-52156 is an effective and selective S1P3 receptor antagonist (Ki: 110 nM).

CS 2100 (1-[[4-Ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl]methyl]-3-azetidinecarboxylic acid) is an S1P1 agonist.

FTY720 is a derivative of ISP-1 (myriocin), a fungal metabolite of the Chinese herb Iscaria sinclarii as well as a structural analog of sphingosine. It is a novel immune modulator that prolongs allograft transplant survival in numerous models by inhibiting lymphocyte emigration from lymphoid organs. FTY720 is phosphorylated by sphingosine kinase, which then acts as a potent agonist at four of the sphingosine-1-phosphate (S1P) receptors (S1P1, S1P3, S1P4, and S1P5). Down-regulation of S1P1 receptors on T and B lymphocytes by FTY720 results in defective egress of these cells from spleen, lymph nodes, and Peyer's patch. azido-FTY720 is a highly photoreactive analog of FTY720 that can be used to identify receptor binding sites for this ligand.

CAY10444 is an S1P3 specific antagonist.

CYM50308 is a high affinity agonist of sphingosine-1-phosphate receptor 4 (S1P4-R) (EC50: 56 nM). CYM50308 has no activity at S1P1-R, S1P2-R and S1P3-R subtypes at concentrations up to 25 μM and it shows 37-fold more selective for S1P4-R than S1P5-R.

Sphingosine-1-phosphate (S1P) is a bioactive lipid that exhibits a broad spectrum of biological activities including cell proliferation, survival, migration, cytoskeletal organization, and morphogenesis. It exerts its activity by binding to five distinct G protein-coupled receptors, S1P1 EDG-1, S1P2 EDG-5, S1P3 EDG-3, S1P4 EDG-6, and S1P5 EDG-8. W140 is an inactive enantiomer of W146, a selective S1P1 antagonist (Ki = 77 nM), that binds to the S1P1 receptor with a Ki of 4.6 μM (2a = W146; 2b = W140 in supplemental material). It exhibits no biological activity in vivo and can therefore serve as an effective control compound for experiments involving W146.

A-971432 is a sphingosine-1-phosphate receptor 5 (S1P5) agonist that is selective for S1P5 over S1P1 and S1P3 (IC50s = 0.006, 0.362, and >10 µM, respectively). It inhibits forskolin-induced cAMP production in CHO cells expressing S1P5 (EC50 = 4.1 nM). A-971432 (1 µM) increases electrical resistance of hCMEC D3 cells in an in vitro blood-brain barrier model, indicating enhanced barrier integrity, and attenuates blood-brain barrier leakage in an R6 2 transgenic mouse model of Huntington's disease when administered at a dose of 0.1 mg kg.[1] [2] A-971432 (0.1 mg kg per day, i.p.) decreases the number of errors made in a horizontal ladder task and increases latency to fall in the rotarod test in R6 2 mice. It also increases spontaneous alternation in the t-maze in aged mice when administered at a dose of 0.1 mg kg.[1] References [1].Hobson, A.D., Harris, C.M., van der Kam, E.L., et al. Discovery of A-971432, an orally bioavailable selective sphingosine-1-phosphate receptor 5 (S1P5) agonist for the potential treatment of neurodegenerative disorders. J. Med. Chem. 58(23), 9154-9170 (2015).[2]. Di Pardo, A., Castaldo, S., Amico, E., et al. Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease. Hum. Mol. Genet. 27(14), 2490-2501 (2018).

GSK1842799 is a selective S1P1 receptor agonist for multiple sclerosis. Upon phosphorylation, GSK1842799 showed subnanomole S1P1 agonist activity with >1000× selectivity over S1P3. GSK1842799 demonstrated good oral bioavailability. On the basis of the favorable in vitro ADME and in vivo PK PD properties as well as broad toxicology evaluations, GSK1842799 was selected as a candidate for further clinical.

TC-SP 14, also known as compound 14, is a highly active and potent S1P1 agonist with oral bioavailability. It exhibits an EC50 value of 0.042 μM, indicating its strong binding affinity to the S1P1 receptor. Notably, its interaction with the S1P3 receptor is minimal, as evidenced by an EC50 value of 3.47 μM. TC-SP 14 demonstrates significant pharmacological effects, including a marked reduction in blood lymphocyte counts and the attenuation of delayed type hypersensitivity response to antigen challenge [1].

Siponimod (BAF-312) hemifumarate, a selective and potent modulator of sphingosine-1-phosphate (S1P) receptors, can be used in the study of multiple sclerosis (MS).

C16 Sphingosine-1-phosphate (C16 S1P) is a derivative of sphingosine-1-phosphate that binds to S1P1/EDG-1, S1P3/EDG-3, and S1P2/EDG-5 receptors with affinities of 115%, 83%, and 103%, respectively, relative to S1P in CHO cells. C16 S1P was increased in postmortem primary open angle glaucoma trabecular meshwork samples.

ASP1126 is a selective and orally active sphingosine-1-phosphate (S1P) agonist with EC50 values of 7.12 nM and 517 nM for hS1P1 and hS1P3, respectively.

Lysosphingomyelin is an endogenous bioactive sphingolipid and a constituent of lipoproteins.1,2It is produced by the removal of the acyl group from sphingomyelin by a deacylase and acts as a precursor in the biosynthesis of sphingosine-1-phosphate . D-erythroLysosphingomyelin is an agonist of the S1P receptors S1P1, S1P2, and S1P3(EC50s = 167.7, 368.1, and 482.6 nM, respectively, for the human receptors).3It is also an agonist of the orphan receptor ovarian cancer G protein-coupled receptor 1 (ORG1) that induces calcium accumulation in cells overexpressing OGR1 (EC50= ~35 nM).4Levels of D-erythrolysosphingomyelin are increased in skin isolated from patients with atopic dermatitis, as well as postmortem brain from patients with Niemann-Pick disease type A, but not type B.2,5L-threolysosphingomyelin is also an S1P1-3agonist (EC50s = 19.3, 131.8, and 313.3 nM, respectively).3This product is a mixture of D-erythroand L-threolysosphingomyelin. [Matreya, LLC. Catalog No. 1321] 1.Ito, M., Kurita, T., and Kita, K.A novel enzyme that cleaves the N-acyl linkage of ceramides in various glycosphingolipids as well as sphingomyelin to produce their lyso formsJ. Biol. Chem.270(41)24370-24374(1995) 2.Nixon, G.F., Mathieson, F.A., and Hunter, I.The multi-functional role of sphingosylphosphorylcholineProg. Lipid Res.47(1)62-75(2008) 3.Im, D.-S., Clemens, J., Macdonald, T.L., et al.Characterization of the human and mouse sphingosine 1-phosphate receptor, S1P5 (Edg-8): Structure-activity relationship of sphingosine1-phosphate receptorsBiochemistry40(46)14053-14060(2001) 4.Meyer zu Heringdorf, D., Himmel, H.M., and Jakobs, K.H.Sphingosylphosphorylcholine-biological functions and mechanisms of actionBiochim. Biophys. Acta1582(1-3)178-189(2002) 5.Rodriguez-Lafrasse, C., and Vanier, M.T.Sphingosylphosphorylcholine in Niemann-Pick disease brain: Accumulation in type A but not in type BNeurochem. Res.24(2)199-205(1999)

VPC 23019 is a competitive antagonist at the S1P1 and S1P3 receptors (pKi= 7.86 and 5.93, respectively). It is also an agonist at the S1P4 and S1P5 receptors (pEC50= 6.58 and 7.07, respectively).

CYM-5541 (ML249) is a selective and allosteric S1P3 receptor agonist.

S1P receptor agonist 2 (compound 1) is a selective agonist of the S1P5 receptor, exhibiting higher selectivity than for S1P1 and or S1P3 receptors. It is useful in the endogenous SIP signaling system and for mitigating or preventing central nervous system (CNS) diseases, including neurodegenerative diseases.