Sphingosine-1-phosphate receptor 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. Disco ...

modulators are a class of drugs used as immunomodulators, most notably in cases of

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

. These drugs have the ability to modulate the G-protein coupled S1P

receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

. Drugs that modulate S1P1 receptors bind to those receptors in

lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...

s and prevent certain lymphoid immune cells from being excreted into the blood and reaching the central nervous system (CNS), leading to

lymphopenia Lymphocytopenia is the condition of having an abnormally low level of lymphocytes in the blood. Lymphocytes are a white blood cell with important functions in the immune system. It is also called lymphopenia. The opposite is lymphocytosis, which re ...

History and development

Discovery

The class of drugs known as S1P

receptor modulator A receptor modulator, or receptor ligand, is a general term for a substance, endogenous or exogenous, that binds to and regulates the activity of chemical receptors. They are ligands that can act on different parts of receptors and regulate activit ...

s came into being with the synthesis of compound FTY720 (

fingolimod Fingolimod, sold under the brand name Gilenya, is an immunomodulating medication, mostly used for treating multiple sclerosis (MS). Fingolimod is a sphingosine-1-phosphate receptor modulator, which sequesters lymphocytes in lymph nodes, prevent ...

) in 1992. The drug was developed following observations of immunosuppressive action in ISP-1 (

myriocin Myriocin, also known as antibiotic ISP-1 and thermozymocidin, is a non-proteinogenic amino acid derived from certain thermophilic fungi. Myriocin is a very potent inhibitor of serine palmitoyltransferase, the first step in sphingosine biosynthe ...

), a natural product derived from the fungus

Isaria sinclairii ''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. Taxonomy ''Isa ...

. Myriocin, see illustration 1, is an untraditional

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

that has showed effectiveness as an

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified in ...

in rats. This led to further investigation of a possible drug-class that could be used in immunosuppressive therapy. 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. 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. 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 Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, ...

. 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. ISP1mod

To enhance its activity a few changes were made to the structure shown in illustration 1. In order to find an active

pharmacophore 300px, An example of a pharmacophore model. A pharmacophore is an abstract description of molecular features that are necessary for molecular recognition of a ligand by a biological macromolecule. IUPAC defines a pharmacophore to be "an ensemble o ...

the structure was simplified by removing

chirality Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from ...

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. As research continued it was discovered that reduction of the

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

and

olefin In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...

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. To further improve the activity and safety the

side chain In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called the "main chain" or backbone. The side chain is a hydrocarbon branching element of a molecule that is attached to a l ...

was shortened from 28 carbons to 14 carbons marked orange on illustration 1. Fingolimodstruct

To find the lead optimization a part of the

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...

side chain was replaced with 1,4-disubstituted phenyl ring. This was done to decrease the bond rotation. The

phenyl ring In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...

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 ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

. Moreover, it was found that FTY720 is 100 times more efficient than Cyclosporin A against

experimental autoimmune encephalomyelitis Experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE), is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with ro ...

(EAE) in an animal model of multiple sclerosis. Fingolimodphosr

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. Researchers figured out at last that these drugs are

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

s and becomes active when being

phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

s. Then the phosphorylated drug binds to sphingosine receptors: not only S1P1, but also S1P3, S1P4 and S1P5. By binding to the S1P receptors, the receptors break down with time and become inactivated. The

myelin sheath Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...

is therefore less likely to break down and stays intact for a longer time. The binding to receptor S1P1 is the one that contributes to the mechanism of action, while the others are thought to produce the unwanted side effects of the drugs. The aim in the future for these drugs is therefore to find chemicals/drugs that can bind more selectively to the S1P1 subtype. Adverse side effect of the drugs at first dose can be

bradycardia Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...

, influenza, back pain, hypertension, headache, cough,

dyspnea Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathing, breathe well enough. The American Thoracic Society defines it as "a subjective experience of brea ...

and diarrhea. With further development of the class of drugs hopefully these side effects will no longer be a big issue.

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. Multiple sclerosis is an

autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...

where immune cells attack the

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

s of the central nervous system and degrade the myelin that protect them. 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. Other possible uses of S1P receptor modulators are as agents against autoimmunity, against cancer and inflammatory diseases like

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

, and in organ transplants to prevent rejection of the transplant.

Sphingosine-1-receptor modulators drugs

(*)In phase III for psoriasis, in phase II for graft vs. host. (**) Is on the market in Russia.

References

{{Lysophospholipid signaling modulators Multiple sclerosis Receptor modulators