Asymmetric Synthesis of Conformationally Constrained Fingolimod Analogues—Discovery of an Orally Active Sphingosine 1-Phosphate Receptor Type-1 Agonist and Receptor Type-3 Antagonist

Zhu, Ran; Snyder, Ashley H.; Kharel, Yugesh; Schaffter, Lisa M.; Sun, Qin; Kennedy, Perry; Macdonald, Timothy L.

doi:10.1021/jm7010172

Cited by 65 publications

(62 citation statements)

References 34 publications

(91 reference statements)

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“…We next evaluated the individual contributions of both of these receptors by delivering VPC01091, a S1P 1 agonist and S1P 3 antagonist. 20 Local sustained release of VPC01091 significantly decreased arteriolar diameters after 3 days in comparison to FTY720-treated tissues (Fig. 3).…”

Section: Fty720-induced Microvascular Remodelingmentioning

confidence: 87%

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

Sefcik

Aronin

Awojoodu

et al. 2011

Tissue Engineering Part A

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Proper spatial and temporal regulation of microvascular remodeling is critical to the formation of functional vascular networks, spanning the various arterial, venous, capillary, and collateral vessel systems. Recently, our group has demonstrated that sustained release of sphingosine 1-phosphate (S1P) from biodegradable polymers promotes microvascular network growth and arteriolar expansion. In this study, we employed S1P receptorspecific compounds to activate and antagonize different combinations of S1P receptors to elucidate those receptors most critical for promotion of pharmacologically induced microvascular network growth. We show that S1P 1 and S1P 3 receptors act synergistically to enhance functional network formation via increased functional length density, arteriolar diameter expansion, and increased vascular branching in the dorsal skinfold window chamber model. FTY720, a potent activator of S1P 1 and S1P 3 , promoted a 107% and 153% increase in length density 3 and 7 days after implantation, respectively. It also increased arteriolar diameters by 60% and 85% 3 and 7 days after implantation. FTY720-stimulated branching in venules significantly more than unloaded poly(D, L-lactic-co-glycolic acid). When implanted on the mouse spinotrapezius muscle, FTY720 stimulated an arteriogenic response characterized by increased tortuosity and collateralization of branching microvascular networks. Our results demonstrate the effectiveness of S1P 1 and S1P 3 receptor-selective agonists (such as FTY720) in promoting microvascular growth for tissue engineering applications.

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Section: Fty720-induced Microvascular Remodelingmentioning

confidence: 87%

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

Sefcik

Aronin

Awojoodu

et al. 2011

Tissue Engineering Part A

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“…10 Authors of this letter show that the alcohol prodrug of these compounds evoked lymphopenia after oral administration in mice and a stereoisomeric mixture of 2a/2b had minimal effects on heart rate changes in rodents relative to 1. As discussed earlier, effects in rodent on bronchoconstriction and heart rate is mediated by the S1P 3 receptor and may not be relevant in a clinical setting where S1P 1 is believed to play a role.…”

mentioning

confidence: 95%

“…11,12 It was anticipated based on previously published work 10 that the stereoisomeric configuration would influence the efficiency of the metabolic conversion of the amino-alcohol prodrugs to the corresponding phosphates, which are the active S1P agonists. To facilitate the identification of the most active isomers, the extent of phosphorylation of the compounds was evaluated after incubation in mouse whole blood.…”

mentioning

confidence: 99%

Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P₁ Receptor Modulator in Clinical Trials

Dhar

Xiao

Xie

et al. 2016

ACS Med. Chem. Lett.

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Clinical validation of S1P receptor modulation therapy was achieved with the approval of fingolimod (Gilenya, 1) as the first oral therapy for relapsing remitting multiple sclerosis. However, 1 causes a dose-dependent reduction in the heart rate (bradycardia), which occurs within hours after first dose. We disclose the identification of clinical compound BMS-986104 (3d), a novel S1P 1 receptor modulator, which demonstrates ligand-biased signaling and differentiates from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model. KEYWORDS: GPCR, S1P1, S1P3, biased signaling L ymphocyte infiltration from blood into sites of inflammation is critical to the pathogenesis of autoimmune diseases and allograft rejection. Gilenya (FTY720, 1) blocks lymphocyte migration through sequestration of lymphocytes in the thymus and secondary lymphoid organs, leading to a marked lymphopenia. 1 Compound 1 is a pro-drug; its phosphorylated form, FTY-P (1-P), binds four out of the five S1P receptors (S1P-1, 3, 4, 5) and elicits a full agonist response in functional assays such as GTP-S binding, ERK phosphorylation, cAMP, and calcium mobilization. Among these four receptors, S1P 1 has been shown to be critically involved in lymphocyte trafficking and agonism of this receptor is responsible for the peripheral blood lymphopenia believed to be key to the efficacy seen with 1. 2,3 Clinical studies have demonstrated a side effect profile of 1 that includes cardiovascular effects (transient bradycardia, sustained blood pressure elevation) as well as a decline in pulmonary function. 4 In rodent studies, S1P 3 activity was shown to play a role in some of the observed acute toxicity of nonselective S1P receptor agonists, including bradycardia, hypertension, and bronchoconstriction. 5,6 As agonism of S1P 3 does not appear to contribute to efficacy, the identification of S1P 1 agonists sparing of S1P 3 has been a primary emphasis of many research programs in this area. 7 However, clinical studies with S1P agonists with selectivity for S1P 1 over S1P 3 have suggested that in humans the heart rate reduction effects are controlled at least in part through agonism of S1P 1 . 8 Additionally, through the course of our own studies it was discovered that simply abolishing S1P 3 agonism was not sufficient to eliminate the acute and chronic pulmonary toxicity elicited in rodents by 1 or by selective S1P 1 full agonists, findings that led us to discontinue our efforts related to S1P 1 full agonists and seek alternative profiles that could overcome these liabilities. 9 In this letter we describe the identification of a differentiated S1P 1 receptor modulator, BMS-986104 (3d), which distinguishes itself from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model.In our search for S1P 1 agonists that could further dissociate efficacy from toxicity, we evaluated...

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“…For example, a compound (VPC01091) with a phenyl cyclopentyl linker is an SPHK2 substrate and the phosphorylated form retains potency as an S1P1 agonist but has negative efficacy at the S1P3 receptor (i.e. inverse agonist) [55]. Thus, VPC01091 is an S1P3 receptor antagonist and does not cause bradycardia in experimental animals (unpublished data).…”

Section: Other S1p Receptor Agonistsmentioning

confidence: 95%

“…Thus, VPC01091 is an S1P3 receptor antagonist and does not cause bradycardia in experimental animals (unpublished data). Curiously, one isomer of VPC01091 is extremely long-lived in vivo; a single oral dose (3 mpk) renders rodents lymphopenic for more than two weeks [55].…”

Section: Other S1p Receptor Agonistsmentioning

confidence: 99%

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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Asymmetric Synthesis of Conformationally Constrained Fingolimod Analogues—Discovery of an Orally Active Sphingosine 1-Phosphate Receptor Type-1 Agonist and Receptor Type-3 Antagonist

Cited by 65 publications

References 34 publications

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P₁ Receptor Modulator in Clinical Trials

Sphingosine 1-phosphate chemical biology

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Asymmetric Synthesis of Conformationally Constrained Fingolimod Analogues—Discovery of an Orally Active Sphingosine 1-Phosphate Receptor Type-1 Agonist and Receptor Type-3 Antagonist

Cited by 65 publications

References 34 publications

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P1 Receptor Modulator in Clinical Trials

Sphingosine 1-phosphate chemical biology

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Product

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Identification and Preclinical Pharmacology of BMS-986104: A Differentiated S1P₁ Receptor Modulator in Clinical Trials