Synthesis and biological evaluation of γ-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists

Foss, Frank W.; Snyder, Ashley H.; Davis, Michael D.; Rouse, Michael; Okusa, Mark D.; Lynch, Kevin R.; Macdonald, Timothy L.

doi:10.1016/j.bmc.2006.10.060

Cited by 154 publications

(110 citation statements)

References 41 publications

(54 reference statements)

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“…FTY720 treatment also led to a decrease in leukocyte infiltration, vascular permeability and peripheral blood lymphocyte counts. The protective effect of FTY720 was reversed with VPC44116, a selective S1P 1 receptor antagonist [63]. Furthermore, SEW2871; a selective S1P 1 agonist, significantly decreased plasma creatinine in a dose response manner with a maximal reduction of ∼70% at a dose of 10 mg/kg (Fig.…”

Section: S1p1 Receptors In Akimentioning

confidence: 85%

Targeting sphingosine 1 phosphate receptor type 1 receptors in acute kidney injury

Okusa

Lynch

2007

Drug Discovery Today: Disease Mechanisms

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Sphingosine 1-phosphate analogs have a multitude of effects with the best characterized one being mediated through sphingosine 1-phosphate type 1 receptors (S1P1 receptor). Currently, S1P1 receptor agonists are being developed and tested for human disease. Because of the potent effect of S1P1 agonists to modulate the immune system, these compounds are ideal for blocking immune mechanisms that mediate acute kidney injury (AKI). This disorder continues to remain an important disease that is characterized by high morbidity and mortality. Currently there are no FDA approved drugs for the treatment of AKI. This review summarizes current knowledge on the mechanism of AKI due to ischemia-reperfusion and early studies that target S1P1 receptors for the treatment and prevention of AKI.Acute kidney injury (AKI) is a burgeoning medical disease. Based upon the National Health Statistics and National Hospital Discharge Survey, between 1979 and 2002 there has been an increase in hospitalization for AKI (ICD9 = 584.0 through 584.9) from 35,000 to 650,000 cases per year (P. Eggers, Am Soc. Nephrol., 2004). Overall mortality has been reported to be 40-60% in critically ill patients [1][2][3]. The estimated annual health care expenditures attributed to hospital-acquired AKI exceed $10 billion [4]. Furthermore there is recognition that there is an increase in the end stage renal disease (ESRD) population due to AKI. In patients suffering from AKI, 13.4% of patients (or 30% of patients with AKI superimposed on chronic kidney disease) will progress to ESRD in 3 years (P. Eggers, Am Soc. Nephrol, 2004). Thus to overcome barriers to successful treatment of AKI, well designed clinical trials will need to be based on a precise understanding of the molecular, cellular and immunological basis of AKI [5]. Novel pharmacological agents need to be tested in preclinical and clinical trials. This review focuses on the pathogenesis of ischemia-reperfusion and one class of agents, agonists of sphingosine 1-phosphate receptors, that are potential agents in the treatment of AKI. Pathogenesis of acute kidney ischemia reperfusion injuryAKI from ischemia is initiated by unfavorable changes in renal blood flow as a consequence of vasospasm, alterations in ultrafiltration coefficient, tubular obstruction and/or back-leak. The renal medulla is particularly susceptible to renal ischemia because of a low oxygen tension (PO 2 of 10-20 mmHg) [6]. With loss of blood flow, oxygen content is reduced even farther due to red blood cell and leukocyte trapping and a decrease in medullary blood flow. Hypoxic injury or reperfusion injury results in endothelial cell dysfunction that alters the balance of vascular tone of vasoactive agents such as endothelin and nitric oxide [7,8,[9][10][11]. In addition Dendritic cell activation of NKT cells and IFN-γ in kidney IRITissue resident macrophages and dendritic cells originate from a heterogeneous population of bone marrow-derived monocytes [23][24][25][26] Sphingosine 1-phosphate (S1P) receptors and analogsSphing...

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Section: S1p1 Receptors In Akimentioning

confidence: 85%

Targeting sphingosine 1 phosphate receptor type 1 receptors in acute kidney injury

Okusa

Lynch

2007

Drug Discovery Today: Disease Mechanisms

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“…Both hexyl (S1P R) [57] and octyl (VPC44116) [58] phenyl amide phosphonates have been characterized. Fortunately, in these cases, receptor affinity did not suffer with the substitution of a phosphonate moiety for phosphate.…”

Section: S1p Receptor Antagonistsmentioning

confidence: 99%

“…Fortunately, in these cases, receptor affinity did not suffer with the substitution of a phosphonate moiety for phosphate. The hexyl phosphonate compound has been shown to have a greater separation in affinities between the S1P1 and S1P3 receptors and thus is more S1P1-selective than the octyl compound [58]. To date, these phenyl amide compounds are the only published S1P1 receptor antagonists.…”

Section: S1p Receptor Antagonistsmentioning

confidence: 99%

“…For example, S1P R and VPC44116 do not evoke lymphopenia in mice, which runs counter to a prediction of the 'functional antagonist' model of FTY720 action. Rather, the antagonist molecules block the lymphopenic activity of at least some S1P1 agonists [57,58]. As potential therapeutic agents, the answer is more nuanced.…”

Section: S1p Receptor Antagonistsmentioning

confidence: 99%

“…As potential therapeutic agents, the answer is more nuanced. Both S1P R and VPC44116 cause increased leakage of Evan's blue dye in lung after a single dose in mice [57,58]. S1P1 agonists such as FTY720 oppose the pulmonary edema provoked by intra-tracheal administration of a pro-inflammatory cytokine [47].…”

Section: S1p Receptor Antagonistsmentioning

confidence: 99%

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Sphingosine 1-phosphate chemical biology

Lynch

Macdonald

2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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A dozen years ago, the term 'S1P' (sphingosine 1-phosphate) was not in the lexicons of scientific literature databases. By early 2008, this query term retrieved well over 1,000 citations from PubMed -about 225 of these appeared in 2007. Indeed, S1P is arguably the most heavily studied lipid molecule at present. What happened to distinguish S1P among many other signaling lipids? We believe that the seminal event was the linking of the investigational drug, FTY720 (fingolimod), to S1P signaling. This realization profoundly altered understanding of S1P biology, revealing both that S1P is prominent in lymphocyte trafficking and that mimicking S1P signaling with an agonist drug can modulate the immune system to considerable therapeutic benefit. Neither fact was known prior to FTY720; indeed, this molecule is testament to the power of chemical biology. In this communication, we attempt to summarize progress to date in S1P chemical biology. S1P biosynthesis and degradationIn mammals, the long chain base sphingosine is formed by amidase catalyzed hydrolysis of ceramides. Sphingosine is phosphorylated by sphingosine kinase types 1 or 2 (SPHK1, SPHK2) to form S1P, which is either converted back to sphingosine by lipid phosphatases or degraded irreversibly by S1P lyase [1]. S1P synthesis occurs in cells (but see reference [2]), thus the existence of S1P in plasma indicates some efflux system is responsible for S1P's appearance. A small fraction of long chain bases lack a double bond (sphinganine (dihydrosphingosine), which is the precursor to ceramide in mammalian sphingolipid anabolism) [3]. Sphinganine is a substrate of SPHK and the product, sphinganine 1-phosphate, is for the most part indistinguishable from S1P in its biologic effects (but see reference [4]). The S1P biosynthetic pathway is widespread among mammalian tissues. S1P concentrations in human and mouse plasma are 200-800 nanoM, where the molecule is nearly all protein-bound. S1P introduced into the mouse vasculature is degraded quickly (T1/2 15 min [5]), which indicates a rapid flux of sphingosine through the pathway outlined above. Mice lacking either SPHK1 or SPHK2 have decreased plasma S1P concentrations [6][7][8], but the reduction is more pronounced in SPHK1 null animals [6]. Disruption of both Sphk1 and Sphk2 gene loci is embryonic lethal in mice [9]. Characterization of the phosphatase(s) that hydrolyze the S1P phosphate monoester has been problematic. Leading candidates for this enzyme are the integral membrane lipid ectophosphatase LPP3 (lipid © 2008 Elsevier B.V. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers tha...

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Multiple Sclerosis

Huryn

2010

Burger's Medicinal Chemistry and Drug Discovery

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Multiple sclerosis ( MS ) is a severe, debilitating disease that affects more than a million individuals worldwide. Unfortunately, most aspects of this disease are poorly understood, thereby making drug discovery efforts particularly challenging. Historically, therapeutics for MS have relied on broad immunosuppression, and therefore these agents cause significant limiting side effects. Many of these older drugs were developed first as cancer therapeutics, and their ability to prevent the proliferation of immune cells was exploited in treating MS patients. Other current frontline therapies include immunosuppressants and immunomodulators that originally found use in inflammatory or other automimmune disorders. Current efforts are focusing on a more subtle approach at immunomodulation that target specific aspects of the immune response or putative MS autoantigens. This chapter provides an overview of currently approved therapies, including small‐molecule and protein‐based therapeutics as well as a more detailed review of promising new approaches, particularly those with a medicinal chemistry component.

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Synthesis and biological evaluation of γ-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists

Cited by 154 publications

References 41 publications

Targeting sphingosine 1 phosphate receptor type 1 receptors in acute kidney injury

Targeting sphingosine 1 phosphate receptor type 1 receptors in acute kidney injury

Sphingosine 1-phosphate chemical biology

Multiple Sclerosis

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