Sphingosine-1-phosphate receptor modulator

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

Sphingosine-1-phosphate receptor modulator
Drug class
Sphingosine-1-phosphate
Class identifiers
UseMultiple Sclerosis (MS), psoriasis, Host vs. graft disease, organ transplant
ATC codeL04AA
Biological targetSphingosine-1-phosphate receptor
Legal status
In Wikidata

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.

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

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
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
Drugs Indication Receptor selectivity Status
  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.

6. Ceralifimod

7. Zectivimod.

References
  1. Dyckman, Alaric J. (13 July 2017). "Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P 1 ) Agonists and Future Perspectives". Journal of Medicinal Chemistry. 60 (13): 5267–5289. doi:10.1021/acs.jmedchem.6b01575. PMID 28291340.
  2. 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. 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. 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. 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. 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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