Sphingosine-1-phosphate receptor modulator

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Sphingosine-1-phosphate receptor modulator
Drug class
Sphingosine 1-phosphate.svg
Sphingosine-1-phosphate
Class identifiers
UseMultiple Sclerosis (MS), psoriasis, Host vs. graft disease, organ transplant
ATC code L04AA
Biological target Sphingosine-1-phosphate receptor
Legal status
In Wikidata

Sphingosine-1-phosphate receptor modulators are a class of drugs used as immunomodulators, most notably in cases of multiple sclerosis.

Contents

These drugs have the ability to modulate the G-protein coupled S1P receptors. Drugs that modulate S1P1 receptors bind to those receptors in lymph nodes and prevent certain lymphoid immune cells from being excreted into the blood and reaching the central nervous system (CNS), leading to lymphopenia. [1] [2] [3] [4]

History and development

Discovery

The class of drugs known as S1P receptor modulators came into being with the synthesis of compound FTY720 (fingolimod) in 1992. The drug was developed following observations of immunosuppressive action in ISP-1 (myriocin), a natural product derived from the fungus Isaria sinclairii. Myriocin, see illustration 1, is an untraditional amino acid that has showed effectiveness as an in vivo immunosuppressant in rats. This led to further investigation of a possible drug-class that could be used in immunosuppressive therapy. [3] The lymphopenia causing mechanism of fingolimod was discovered in 2002 and was found to be due to the drug's ability to alter the S1P1 receptor in the secondary lymphs. Furthermore, fingolimod was found to modulate receptors 1-5 of the sphingosine-1-phosphate class. Fingolimod is the first-in-class discovered drug that act as a sphingosine-1-receptor modulator. Even though it has the drawback of not being a selective receptor modulator it has passed all clinical drug trials and was approved for the market in USA in 2010. [2] [5] In the beginning the focus of developing a drug from myriocin was to find an immunosuppressant drug that could be used to prevent rejection of organs during and after a transplant. But fingolimod was later found to be more effective against multiple sclerosis. [6] The mechanism that lead to the desired effect of fingolimod is due to the modulation of S1P1 receptors and the future development of this drug class is therefore aiming for more selective modulators than fingolimod.

Development

Researchers figured out that the metabolite ISP-1, myriocin, was 10 times more active than cyclosporin A. [7] The first drug FTY720 (fingolimod) was developed from ISP-1. Because the metabolite itself is an amphiphilic compound and, which represent poor cellular permeability and oral bioavailability FTY720, fingolimod, was synthesized to improve these properties in vivo. [1] [6] [7]

Illustration 1: The parent compound ISP-1 (myriocin). The coloured groups represent the structural changes that were made to the compound to synthesize fingolimod. ISP1mod.jpg
Illustration 1: The parent compound ISP-1 (myriocin). The coloured groups represent the structural changes that were made to the compound to synthesize fingolimod.

To enhance its activity a few changes were made to the structure shown in illustration 1. In order to find an active pharmacophore the structure was simplified by removing chirality and functionality. The first chiral group, marked red on illustration 1, was removed by the conversion of the carboxyl acid to 2-amino-1,2-propane diol. [7]

As research continued it was discovered that reduction of the ketone and olefin groups, marked purple on illustration 1, was tolerated. Furthermore, the remaining 3-hydroxyl and 4-hydroxyl groups marked green on illustration 1 were non-essential to its activity. They were therefore removed from the compound resulting in an achiral intermediate and daughter compound. These changes of ISP-1 resulted in continued improvements in the profile of the compound. [7] [8]

To further improve the activity and safety the side chain was shortened from 28 carbons to 14 carbons marked orange on illustration 1. [7]

Illustration 2: The product FTY720 (fingolimod) is derived from ISP-1 Fingolimodstruct.jpg
Illustration 2: The product FTY720 (fingolimod) is derived from ISP-1

To find the lead optimization a part of the fatty acid side chain was replaced with 1,4-disubstituted phenyl ring. This was done to decrease the bond rotation. The phenyl ring was moved along the side chain to find its optimal position. These efforts resulted in the two carbon linkers from the polar head group to the phenyl moiety. The resulting product was FTY720 as shown in illustration 2 and its activated, phosphorylated form in illustrations 3a and 3b. Research showed that FTY720 had the same efficacy as ISP-1 in vitro. Moreover, it was found that FTY720 is 100 times more efficient than Cyclosporin A against experimental autoimmune encephalomyelitis (EAE) in an animal model of multiple sclerosis. [7] [9]

Illustration 3a: (R)-phosphorylated fingolimod Fingolimodphosr.jpg
Illustration 3a: (R)-phosphorylated fingolimod
Illustration 3b: (S)-phosphorylated fingolimod Fingolimodphos.jpg
Illustration 3b: (S)-phosphorylated fingolimod

Pharmacology

At first the mechanism of action of the first drug in this class (fingolimod) was unknown and great efforts were made to figure out its mechanism of action. [1] Researchers figured out at last that these drugs are prodrugs and becomes active when being phosphorylated by kinases. [10] Then the phosphorylated drug binds to sphingosine receptors: not only S1P1, but also S1P3, S1P4 and S1P5. [2] By binding to the S1P receptors, the receptors break down with time and become inactivated. [10] The myelin sheath is therefore less likely to break down and stays intact for a longer time. [2]

The binding to receptor S1P1 is the one that contributes to the mechanism of action, [6] while the others are thought to produce the unwanted side effects of the drugs. [10] The aim in the future for these drugs is therefore to find chemicals/drugs that can bind more selectively to the S1P1 subtype. [2]

Adverse side effect of the drugs at first dose can be bradycardia, influenza, back pain, hypertension, headache, cough, dyspnea and diarrhea. With further development of the class of drugs hopefully these side effects will no longer be a big issue. [10]

Clinical use

The first S1P receptor modulator available on the market was fingolimod. Fingolimod was approved and released on the market in USA in 2010 as an anti-multiple sclerosis drug. [10]

Multiple sclerosis is an autoimmune disease where immune cells attack the neurons of the central nervous system and degrade the myelin that protect them. [11]

There is no cure for multiple sclerosis, but disease modifying therapies (DMTs) can slow disease progression and reduce the frequency and severity of relapses. Whereas S1P receptor modulators work by modulating the immune system, other DMTs have different mechanisms, such as suppressing the immune system. [12]

Other possible uses of S1P receptor modulators are as agents against autoimmunity, against cancer and inflammatory diseases like Alzheimer's disease, and in organ transplants to prevent rejection of the transplant. [1] [3]

Sphingosine-1-receptor modulators drugs

DrugsIndicationReceptor selectivityStatus
  1. Fingolimod [2]
Multiple sclerosis (MS) S1P1, S1P3, S1P4 and S1P5 FDA approved 2010, EMA approved 2011
2. Ozanimod [2] Multiple sclerosis (MS) and ulcerative colitits (UC) S1P1 and S1P5 FDA approved 2020
3. Siponimod [2] Multiple sclerosis (MS) S1P1 and S1P5 FDA Approved 2019, EMA approved 2020
4. Ponesimod [2] Multiple sclerosis (MS), psoriasis and graft vs. host disease S1P1 FDA Approved 2021, In Phase III clinical trials and Phase II trials. (*)

(*)In phase III for psoriasis, in phase II for graft vs. host.

(**) Is on the market in Russia.

5. Etrasimod  : approved by FDA and marketed by Pfizer as Velsipity. Inhibits S1P1 selectively.

6. Ceralifimod. Selective inhibitor of S1P1 and S1P5.

7. Zectivimod. Selective inhibitor of S1P1.

8. Cenerimod. Selective inhibitor of S1P1 and S1P5.

Related Research Articles

<span class="mw-page-title-main">Fingolimod</span> Chemical compound

Fingolimod, sold under the brand name Gilenya, is an immunomodulating medication, used for the treatment of multiple sclerosis. Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction. It has been reported to reduce the rate of relapses in relapsing-remitting multiple sclerosis by approximately one-half over a two-year period.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

<span class="mw-page-title-main">Myriocin</span> Chemical compound

Myriocin, also known as antibiotic ISP-1 and thermozymocidin, is a non-proteinogenic amino acid derived from certain thermophilic fungi.

Sphingosine-1-phosphate (S1P) is a signaling sphingolipid, also known as lysosphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.

Ceramidase is an enzyme which cleaves fatty acids from ceramide, producing sphingosine (SPH) which in turn is phosphorylated by a sphingosine kinase to form sphingosine-1-phosphate (S1P).

The RAR-related orphan receptors (RORs) are members of the nuclear receptor family of intracellular transcription factors. There are three forms of ROR, ROR-α, -β, and -γ and each is encoded by a separate gene, RORA, RORB, and RORC respectively. The RORs are somewhat unusual in that they appear to bind as monomers to hormone response elements as opposed to the majority of other nuclear receptors which bind as dimers. They bind to DNA elements called ROR response elements (RORE).

<span class="mw-page-title-main">S1PR1</span> Protein and coding gene in humans

Sphingosine-1-phosphate receptor 1, also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded by the S1PR1 gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P). S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5). S1PR1 was originally identified as an abundant transcript in endothelial cells and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation. In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking.

<span class="mw-page-title-main">S1PR2</span> Protein and coding gene in humans

Sphingosine-1-phosphate receptor 2, also known as S1PR2 or S1P2, is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P).

<span class="mw-page-title-main">S1PR5</span> Protein-coding gene in the species Homo sapiens

Sphingosine-1-phosphate receptor 5 also known as S1PR5 is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Hence this receptor is also known as S1P5.

<span class="mw-page-title-main">Metabotropic glutamate receptor 2</span> Mammalian protein found in humans

Metabotropic glutamate receptor 2 (mGluR2) is a protein that, in humans, is encoded by the GRM2 gene. mGluR2 is a G protein-coupled receptor (GPCR) that couples with the Gi alpha subunit. The receptor functions as an autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons.

<i>Isaria sinclairii</i> Species of fungus

Isaria sinclairii is a species of entomopathogenic fungus mostly infecting the underground nymphs of cicadas. It produces myriocin, from which the synthetic drug fingolimod, a treatment for multiple sclerosis, was developed.

<span class="mw-page-title-main">Sphingosine-1-phosphate receptor</span>

The sphingosine-1-phosphate receptors are a class of G protein-coupled receptors that are targets of the lipid signalling molecule Sphingosine-1-phosphate (S1P). They are divided into five subtypes: S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5.

<span class="mw-page-title-main">Ponesimod</span> Medication for the treatment of multiple sclerosis

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<span class="mw-page-title-main">Ozanimod</span> Medication

Ozanimod, sold under the brand name Zeposia, is an immunomodulatory medication for the treatment of relapsing multiple sclerosis and ulcerative colitis. It acts as a sphingosine-1-phosphate receptor (S1PR) agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation.

A drug class is a group of medications and other compounds that have similar chemical structures, the same mechanism of action, similar modes of action, and/or are used to treat the similar diseases. The Food and Drug Administration (FDA) has worked on classifying and licensing new medications for many years. However, the FDA's Drug Evaluation and Research Center categorizes these new medications based on both their chemical and therapeutic class.

<span class="mw-page-title-main">A-971432</span> Chemical compound

A-971432 is an orally bioavailable selective agonist of sphingosine-1-phosphate receptor 5 (S1PR5) discovered at AbbVie. It was discovered using high-throughput chemistry. S1P5 agonists have been proposed as an innovative mechanism for the treatment of neurodegenerative disorders such as Alzheimer's disease and lysosomal storage disorders such as Niemann–Pick disease. Stimulation of S1PR5 with A-971432 has been shown to preserve blood-brain barrier integrity and exert a therapeutic effect in an animal model of Huntington’s disease.

<span class="mw-page-title-main">Siponimod</span> Chemical compound

Siponimod, sold under the brand name Mayzent, is a selective sphingosine-1-phosphate receptor modulator for oral use that is used for multiple sclerosis (MS). It is intended for once-daily oral administration.

<span class="mw-page-title-main">ACP-105</span> Chemical compound

ACP-105 is a drug which acts as a selective androgen receptor modulator (SARM). It has been investigated for potential use in the treatment of age-related cognitive decline. The drug has been found to reduce anxiety-like behavior in a mouse model of Alzheimer's disease when administered alone, as well as enhance spatial memory when coadministered with the selective estrogen receptor β agonist AC-186. ACP-105 is an aniline SARM and is related to AC-262536 and vosilasarm (RAD140).

Edward Roberts FRSC., is a British-born American scientist with expertise in biochemistry and synthetic organic chemistry. He is recognized for his significant contributions to medicinal chemistry, the design and discovery of new medicines in the development of novel therapeutics.

<span class="mw-page-title-main">Etrasimod</span> Medication

Etrasimod, sold under the brand name Velsipity, is a medication that is used for the treatment of ulcerative colitis (UC). It is a selective sphingosine-1-phosphate (S1P) receptor modulator that modifies the activity of the immune system. It is taken by mouth.

References

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  2. 1 2 3 4 5 6 7 8 9 Park, Soo-Jin; Im, Dong-Soon (1 January 2017). "Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery". Biomolecules & Therapeutics. 25 (1): 80–90. doi:10.4062/biomolther.2016.160. PMC   5207465 . PMID   28035084.
  3. 1 2 3 Adachi, Kunitomo; Chiba, Kenji (6 September 2007). "FTY720 story. Its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology". Perspectives in Medicinal Chemistry. 1: 11–23. doi:10.1177/1177391X0700100002. PMC   2754916 . PMID   19812733.
  4. ↑ Pelletier, Daniel; Hafler, David A. (26 January 2012). "Fingolimod for Multiple Sclerosis". New England Journal of Medicine. 366 (4): 339–347. doi:10.1056/NEJMct1101691. PMID   22276823.
  5. ↑ Mao-Draayer, Yang; Sarazin, Jeffrey; Fox, David; Schiopu, Elena (February 2017). "The sphingosine-1-phosphate receptor: A novel therapeutic target for multiple sclerosis and other autoimmune diseases". Clinical Immunology. 175: 10–15. doi:10.1016/j.clim.2016.11.008. PMC   5315594 . PMID   27890706.
  6. 1 2 3 Demont, Emmanuel H.; Andrews, Benjamin I.; Bit, Rino A.; Campbell, Colin A.; Cooke, Jason W. B.; Deeks, Nigel; Desai, Sapna; Dowell, Simon J.; Gaskin, Pam; Gray, James R. J.; Haynes, Andrea; Holmes, Duncan S.; Kumar, Umesh; Morse, Mary A.; Osborne, Greg J.; Panchal, Terry; Patel, Bela; Perboni, Alcide; Taylor, Simon; Watson, Robert; Witherington, Jason; Willis, Robert (9 June 2011). "Discovery of a Selective S1P 1 Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate". ACS Medicinal Chemistry Letters. 2 (6): 444–449. doi:10.1021/ml2000214. PMC   4018134 . PMID   24900328.
  7. 1 2 3 4 5 6 Yeung, Bryan KS (August 2011). "Natural product drug discovery: the successful optimization of ISP-1 and halichondrin B". Current Opinion in Chemical Biology. 15 (4): 523–528. doi:10.1016/j.cbpa.2011.05.019. PMID   21684798.
  8. ↑ Gilmore, John L.; Sheppeck, James E.; Watterson, Scott H.; Haque, Lauren; Mukhopadhyay, Parag; Tebben, Andrew J.; Galella, Michael A.; Shen, Ding Ren; Yarde, Melissa; Cvijic, Mary Ellen; Borowski, Virna; Gillooly, Kathleen; Taylor, Tracy; McIntyre, Kim W.; Warrack, Bethanne; Levesque, Paul C.; Li, Julia P.; Cornelius, Georgia; D’Arienzo, Celia; Marino, Anthony; Balimane, Praveen; Salter-Cid, Luisa; Barrish, Joel C.; Pitts, William J.; Carter, Percy H.; Xie, Jenny; Dyckman, Alaric J. (14 July 2016). "Discovery and Structure–Activity Relationship (SAR) of a Series of Ethanolamine-Based Direct-Acting Agonists of Sphingosine-1-phosphate (S1P 1 )". Journal of Medicinal Chemistry. 59 (13): 6248–6264. doi:10.1021/acs.jmedchem.6b00373. PMID   27309907.
  9. ↑ Adachi, Kunitomo; Kohara, Toshiyuki; Nakao, Noriyoshi; Arita, Masafumi; Chiba, Kenji; Mishina, Tadashi; Sasaki, Shigeo; Fujita, Tetsuro (April 1995). "Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1,3-propanediols: Discovery of a novel immunosuppressant, FTY720". Bioorganic & Medicinal Chemistry Letters. 5 (8): 853–856. doi:10.1016/0960-894X(95)00127-F.
  10. 1 2 3 4 5 Subei, Adnan M.; Cohen, Jeffrey A. (July 2015). "Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis". CNS Drugs. 29 (7): 565–575. doi:10.1007/s40263-015-0261-z. PMC   4554772 . PMID   26239599.
  11. ↑ "Multiple Sclerosis Information Page | National Institute of Neurological Disorders and Stroke". www.ninds.nih.gov. Retrieved 2017-10-02.
  12. ↑ Liu, Zhuoyi; Liao, Qiao; Wen, Haicheng; Zhang, Yihao (June 2021). "Disease modifying therapies in relapsing-remitting multiple sclerosis: A systematic review and network meta-analysis". Autoimmunity Reviews. 20 (6): 102826. doi:10.1016/j.autrev.2021.102826. S2CID   233325057.
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