Synthesis and SAR studies of a novel class of S1P1 receptor antagonists

Nakamura, Tsuyoshi; Yonesu, Kiyoaki; Mizuno, Yumiko; Suzuki, Chie; Sakata, Yuki; Takuwa, Yoh; Nara, Futoshi; Satoh, Susumu

doi:10.1016/j.bmc.2007.02.048

Cited by 14 publications

(9 citation statements)

References 25 publications

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“…26 For the receptor-binding assay, [ 33 P]Sph-1-P was enzymatically synthesized from sphingosine and [g-33 P]ATP using a recombinant murine sphingosine kinase. 27 Human S1P 1 -expressing cells 28 were seeded into 12-well plates (1Â10 6 cells per well) and cultured overnight.…”

Section: Camp and Receptor-binding Assaymentioning

confidence: 99%

Ascotricins A and B, novel antagonists of sphingosine-1-phosphate receptor 1 from Ascotricha chartarum Berk. SANK 14186

et al. 2009

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Ascotricins A and B were isolated as novel sphingosine-1-phosphate receptor 1 (S1P 1 ) antagonists from a cultured broth of a fungus identified as Ascotricha chartarum Berk. SANK 14186. The two compounds were purified by solvent extraction, reversedphase (RP) column chromatography and a preparative RP-HPLC. The structures were determined by various NMR experiments and by LC/MS and GC/MS analyses. The S1P 1 antagonist activities were measured by a cyclic AMP assay using S1P 1 -expressing cells and the IC 50 values were 8.2 and 1.8 lM, respectively. In a [ 33 P]sphingosine-1-phosphate/S1P 1 -binding assay, those values were 120 and 39 lM, and in a migration assay using human umbilical vein endothelial cells (HUVECs), they were 94 and 28 lM, respectively. Thus, ascotricins A and B are novel S1P 1 antagonists showing an inhibition activity toward HUVEC migration. Keywords: Ascotricha chartarum; ascotricins A and B; HUVEC; S1P 1 antagonist; sphingosine-1-phosphate INTRODUCTION Sphingosine-1-phosphate (Sph-1-P) is an intermediate in the sphingomyelin degradation pathway 1 and is also a bioactive lipid messenger. Sph-1-P provokes a variety of cellular responses, including proliferation, prolongation of survival, cytoskeleton rearrangement, etc. 2,3 The first breakthrough in Sph-1-P research was finding its receptor, the endothelial differentiation gene-1/Sphingosine-1-phosphate receptor 1 (Edg-1/S1P 1 ) 4 . Sph-1-P promoted proliferation, migration and tube formation of vascular endothelial cells through S1P 1 , 5-7 and the phenotype of S1P 1 homozygous knockout mice strongly indicated that S1P 1 was indispensable for angiogenesis. 8,9 The second expansion of Sph-1-P research was re-finding S1P 1 as a pharmacological target of a new immunosuppressant, FTY720 (Fingolimod). 10,11 The active metabolite of FTY720 stimulated S1P 1 as do other synthetic S1P 1 agonists and caused lymphopenia and the resultant immunosuppression. 10-12 Currently, FTY720 is in an ongoing developmental stage in clinical trials as a novel immunosuppressant for multiple sclerosis.Although the current physiological research for Sph-1-P has shifted to S1P 1 agonists and to lymphopenia, the relationship of S1P 1 and angiogenesis has not yet been sufficiently studied. A few potent S1P 1 antagonists have been discovered, 13,14 but their capacity as angiogenesis inhibitors has not yet been examined. To obtain a functional S1P 1 antagonist, we searched for one in microorganisms because several microorganisms have sphingolipid synthesis systems, and microbial secondary metabolites are thought to be attractive sources of Sph-1-P analogs.

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Section: Camp and Receptor-binding Assaymentioning

confidence: 99%

Ascotricins A and B, novel antagonists of sphingosine-1-phosphate receptor 1 from Ascotricha chartarum Berk. SANK 14186

et al. 2009

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“…Target indications are autoimmune diseases such as rheumatoid arthritis, psoriasis and multiple sclerosis, as well as organ transplantation. Additionally, Daiichi Sankyo has reported efforts to develop S1P1 antagonists for the treatment of cardiovascular disease and angiogenesis [95] .…”

Section: Daiichi Sankyo Comentioning

confidence: 99%

Recent progress in the development of selective S1P1 receptor agonists for the treatment of inflammatory and autoimmune disorders

Buzard

Thatte

Lerner

et al. 2008

Expert Opinion on Therapeutic Patents

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Background : The sphingosine-1-phosphate receptor 1 (S1P1) belongs to the endothelial differentiation gene family of G-protein-coupled receptors involved in embryonic development, cellular differentiation and survival, adherence and tight junction assembly, and leukocyte trafficking. In vivo S1P1 is required for egress of thymocytes into the blood and of naive lymphocytes from secondary lymphoid organs back into the lymph. Downregulation of S1P1 disrupts lymphocyte migration, tissue homing and recirculation. To explore the immunomodulatory potential of S1P1, pharma is developing S1P1-selective agonists for treating autoimmune and inflammatory disorders. FTY720 (fingolimod, Novartis AG), a nonselective S1P1 agonist that induces sustained lymphopenia, is a promising pseudolipid aminodiol prodrug that has been shown in preclinical and early clinical trials to be effective in suppressing various autoimmune conditions and to aid in acute organ transplant, and is currently in pivotal Phase III clinical trials for relapsing-remitting multiple sclerosis. Objective : In this review article, we outline recent advances made in the discovery and patenting of new small-molecule S1P1 selective agonists and summarize a rapidly growing body of intellectual property. Conclusion : Fingolimod-like S1P1 agonists with a novel mechanism of action have emerged as promising immunosuppressants. S1P1 agonists induce T-cell sequestration in lymph nodes and Peyer's patches, diminishing their ability to reach distant sites and cause pathology. Preclinical studies have already provided preliminary evidence that low-dose treatment with fingolimod in conjunction with subtherapeutic doses of ciclosporin A and tacrolimus enable potent immunosuppression in the absence of immediately serious side effects. Future efforts will determine whether S1P1 agonists do indeed synergize with existing DMAs to create new mutidrug paradigms with superior efficacy and safety for the treatment of autoimmune diseases and the prevention of organ transplant rejection.

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“…[12][13][14] HUVEC were maintained with HuMedia-EG2 medium. CHO-S1P 1 cells were cultured with a-Minimum Essential Medium containing 10% (v/v) dialyzed fetal bovine serum (SAFC Biosciences, Lenexa, KS, U.S.A.), 100 units/ ml penicillin G sodium, 100 mg/ml streptomycin sulfate, and 125 nM methotrexate without ribonucleosides and deoxyribonucleosides.…”

Section: General Reagents and Animalsmentioning

confidence: 99%

“…14) These cells were maintained in the suitable medium mentioned above with 200 mg/ml Hygromycin. For the measurement of S1P 2 and S1P 3 signaling, intact CHO-S1P 2 cells and CHO-S1P 3 cells were used, respectively.…”

Section: General Reagents and Animalsmentioning

confidence: 99%

“…14) For the measurement of Ca 2ϩ signaling in CHO-S1P 1-4 cells, 100 nM, 100 nM, 10 nM, and 10 mM Sph-1-P were used as a stimulant, respectively, according to each cellular reactivity. 16) HUVEC were suspended in HuMedia-EB2 medium containing 1% (v/v) fetal bovine serum, 1 mg/ml hydrocortisone, 50 mg/ml gentamycin, 50 ng/ml amphotericin B, and 10 mg/ml heparin; and then 2500 of the cells were added to 96-well plates and cultured overnight.…”

Section: Sph-1-p Receptor Subtype Specificity Of Compoundmentioning

confidence: 99%

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A Novel Sphingosine-1-Phosphate Receptor 1 Antagonist Prevents the Proliferation and Relaxation of Vascular Endothelial Cells by Sphingosine-1-Phosphate

Yonesu

Nakamura

Mizuno

et al. 2010

Biological & Pharmaceutical Bulletin

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Sphingosine-1-phosphate (Sph-1-P) is a bioactive plasma lipid which affects cell proliferation and migration, etc., through 5 receptors: sphingosine-1-phosphate receptors 1 (S1P 1 ) to 5 (S1P 5 ).1) Among these receptors, S1P 1 is the most studied and attractive pharmacological target because the S1P 1 agonism provokes lymphopeina 2) and immunosuppression in vivo. Meanwhile, S1P 1 antagonism is supposed to inhibit angiogenesis. 3,4) In the case of agonist compounds, the non-selective Sph-1-P receptor agonist FTY720 (fingolimod, Novartis International AG, Basel, Switzerland) is pre-registered as a drug of multiple sclerosis. Additionally, the S1P 1 specific agonist R-3477 (Actelion Pharmaceuticals Ltd., Basel, Switzerland) is being evaluated in Phase II and I studies as an immunosuppressant for autoimmune disease and organ transplantation, respectively. In the case of antagonist compounds, a preclinical report showed that the small interfering RNA for S1P 1 inhibited tumor growth 5) ; nevertheless, there have been no clinical reports on a chemical compound for the treatment of angiogenic diseases, such as diabetic retinopathy and solid tumors. This is presumably because there are few S1P 1 antagonists that are potent and selective in vivo.Both S1P 1 and S1P 3 also play a role in cardiovascular regulation. The intravenous (i.v.) administration of Sph-1-P at high doses of 100-200 mg/kg caused bradycardia in anesthetized rats.6,7) Moreover, the heart rate of S1P 3 homozygous knockout mice was unchanged by Sph-1-P administration. 7)These results indicate that Sph-1-P caused bradycardia via S1P 3 in the heart, at least in the case of mice. On the other hand, i.v. administration of Sph-1-P at a low dose of 10 mg/kg provoked transient hypotension without affecting the heart rate in anesthetized rats.6) In this case, it is expected that Sph-1-P caused vasodilation on the vascular endothelial cells via S1P 1 and S1P 3 , followed by activation of the endothelial isoform of nitric oxide synthase and NO production. [8][9][10][11] We previously reported that a S1P 1 antagonist, designated as chemical lead 2, showed anti-angiogenesis activity in a rabbit cornea model and inhibition of the swelling of mouse feet in an anti-type II collagen antibody-induced arthritis model. 12) Afterwards, we synthesized derivatives of chemical lead 2 to obtain more effective S1P 1 antagonists and determined the representatives, named as compounds 1 to 5. The aim of this study is to elucidate whether the derivatives inhibit the effect of Sph-1-P both in vitro and in vivo. Therefore, here we describe the Sph-1-P antagonistic activity of the representative derivatives, compounds 1 to 5, through several in vitro and in vivo assays focusing on the proliferation, migration, tube formation, and relaxation of vascular endothelial cells. A sphingosine-1-phosphate receptor 1 (S1P 1 ) antagonist is expected to be an anti-angiogenic compound; however, there are few reports that demonstrated that a S1P 1 inhibitor improved the disease state in an angiogeni...

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Synthesis and SAR studies of a novel class of S1P1 receptor antagonists

Cited by 14 publications

References 25 publications

Ascotricins A and B, novel antagonists of sphingosine-1-phosphate receptor 1 from Ascotricha chartarum Berk. SANK 14186

Ascotricins A and B, novel antagonists of sphingosine-1-phosphate receptor 1 from Ascotricha chartarum Berk. SANK 14186

Recent progress in the development of selective S1P1 receptor agonists for the treatment of inflammatory and autoimmune disorders

A Novel Sphingosine-1-Phosphate Receptor 1 Antagonist Prevents the Proliferation and Relaxation of Vascular Endothelial Cells by Sphingosine-1-Phosphate

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