Aprepitant

Aprepitant is a chemical compound that belongs to a class of drugs called substance P antagonists (SPA). It mediates its effect by acting on neurokinin 1 receptor.

Aprepitant is manufactured by Merck & Co. under the brand name Emend for prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) and for prevention of postoperative nausea and vomiting. It was approved by the FDA in 2003.

Aprepitant may also be useful in the treatment of cyclic vomiting syndrome but there are few studies to date.

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Introduction

Acute or delayed CINV is an unpleasant side effect experienced by over 80% of patients who undergo initial and repeated highly emetogenic cancer chemotherapy, for example Cisplatin in combination with other antiemetic agents. Throughout the 1990's a noticeable increase occurred in the number of diagnosed cancer patients undergoing chemotherapy and therefore experiencing CINV. As a result of this, towards the end of the decade initial research was conducted to try to develop a drug that eases the severity and decreasing the likelihood of CINV, and after several years of research Merck & Co. successfully developed a drug known as Emend.

The active substance of Emend is aprepitant, which is effective in helping to prevent CINV because it antagonizes the NK1 receptor. This receptor is located at the brain stem nuclei of the dorsal vagal complex and is a crucial part of the regulation of emesis (vomiting). This is due to the receptor binding with substance P, a peptide neurotransmitter.

Structure and properties of aprepitant

While the common name for the molecule above is aprepitant its chemical name is 5-[[(2S,3R)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl]-1,2-dihydro-1,2,4-triazol-3-one) This basically means that aprepitant is made up of a morpholine core with two substituents attached to adjacent ring carbons. These substitute groups are trifluoromethylated phenyl ethanol and fluorophenyl group. Aprepitant also has a third substituent (triazolinone) which is joined to the morpholine ring nitrogen. This means that aprepitant is made up of three chiral centres very close together which combine to produce an amino acetal arrangement. It also means that the empirical formula of the substance is C₂₃H₂₁F₇N₄O₃.

The 'morpholine' component of aprepitant is the base of the substance and is a type of heterocyclic compound. The boiling point of morpholine is 129°C, which is relatively high. This could be due to the intermolecular force of hydrogen bonding occurring between the oxygen and hydrogen and between the nitrogen and hydrogen atoms. It would be though that because of the hydrogen bonding the molecule is likely to be polar. However, it is insoluble in water and soluble in non polar solutions. This would therefore support the hypothesis that morpholine is a non-polar molecule.

The 'fluorophenyl' component of aprepitant is a type of halogenoarene. Fluorphenyl has a boiling point which is far less than morpholine. This could be caused by the majority of the intermolecular forces being dispersion, with the only dipole-dipole interaction forces coming from the bond between fluorine and carbon, and there not being any hydrogen bonding in the molecule. Fluorephenyl is an example of a resonance structure. That way, Fluorphenyl is not very reactive.

Another component of aprepitant is 'triazolinone'. This compound has oxygen double bonded to a carbon which is bonded to nitrogen and therefore forms an amide functional. It also contains an actual amide. Triazolinone has a large number of nitrogens, which means that there is a large amount of dipole-dipole and hydrogen bonding. This is because when nitrogen bonds with carbon a dipole-dipole interaction occurs and when nitrogen a bonds with the hydrogen, hydrogen bonding occurs. It could therefore be hypothesises that because of this the triazolinon component of aprepitant would have a reasonable high boiling point and would be reasonable stable. Triazolinon is also soluble in water but not soluble in non polar solutions. It could therefore be suggested that triazolinon is a polar molecule.

The final component of aprepitant is trifluoromethylated phenyl ethanol. This particle compound has an alcohol functional group as well as two halocarbon functional groups where fluorine is bonded to a carbon atom. Because of the numerous fluorine atoms in the molecule there would be a reasonable large amount of dipole-dipole interaction which occurs when the carbon is bonded to the fluorine. Trifluoromethylated phenyl ethanol also has oxygen bonded with hydrogen and therefore has hydrogen bonding. This would mean that its boiling point and stability would be reasonable high, but not as high as triazolinone which has more dipole/dipole and hydrogen bonding. Trifluoromethylated phenyl ethanol is also soluble in water but not in a non polar solution. It is therefore more than likely that it is a polar molecule.

When all four components are joined together aprepitant is formed. Aprepitant is an off-white crystalline solid which has a molecular weight of around 534.53. It has a very limited solubility in water. It does have a reasonable high solubility in non-polar molecules such as oils. This would therefore suggest that aprepitant as a whole, despite having components that are polar, is a non-polar substance.

Synthesis

Shortly after Merck initiated research into the reducing the severity and likelihood of CINV they discovered that aprepitant is effective prevention of it. Researchers worked on coming up with a process to create aprepitant, and within a short period they came up with effective synthesis of the substance. This original synthesis was deemed to be workable and proved to be a crucial step in achieving commercialization; however, Merck decided that the process was not environmentally sustainable. This was due to the original synthesis requiring six steps many of which needed dangerous chemicals such as sodium cyanide, dimethyltitanocene, and gaseous ammonia.

In addition to this, for the process to be effective cryogenic temperatures were needed for some of the steps and other steps produced hazardous by products such as methane and magnesium chloride. The environmental concerns of the synthesis of aprepitant became so great that Merck research team decide to withdraw the drug from clinical trials and attempt to create a different synthesis of aprepitant.

The gamble of taking the drug out of clinical trials proved to be successful when shortly afterwards the team of Merck researchers came up with an alternative and more environmentally friendly synthesis of aprepitant. The new process was works by four compounds of similar size and complexity being fused together. This therefore is a much simpler process and requires only three steps, half the number of the original synthesis.

The new process begins by enantiopure trifluoromethylated phenyl ethanol (Red) being joined to a racemic morpholine precursor (Blue). This results the wanted isomer crystallizing on the top of the solution and the unwanted isomer remaining in the solution. The unwanted isomer is then converted to the wanted one by the chemist controlling the reaction conditions and a process known as crystallization-induced asymmetric transformation occurring. By the end of this step a secondary amine, the base of the drug, is formed.

The second step involves the fluorophenyl group (Black) being attached to the morpholine ring (Blue). Once this has been achieved the third and final step can initiated. This step involved a side chain of triazolinone being added (Green) to the ring. Once this step has been successfully completed a stable molecule of aprepitant has been produced.

This more streamline route not only yields around 76% more aprepitant than the original process but also reduces the operating cost by a significant amount. In addition to this the new process also reduces the amount of solvent and reagents required by about 80% and saved an estimated 340,000L per a ton of aprepitant produced.

As a result of the improvements in the efficiency and reduction of environmental impacts of the synthesis of aprepitant, several social benefits have occurred. The most noticeable of which is a reduction in the price of the drug. This has resulted in a greater number of patients having access to it, which therefore has caused a decrease in the number of people that undergo chemotherapy experiencing CINV. The improvements in the synthesis process have also resulted in a decrease in the number long-term detrimental to the natural environment, due to elimation of hazardous chemicals from the procedure.

Drug development

Once the effective synthesis of aprepitant was discovered, the next step taken by Merck was to develop a pharmaceutical drug that incorporates the active substance in it.

Researches began to analyse aprepitant and make observations about its chemical and physical properties. It was discovered that the substance has a low aqueous solubility. As a result of this the product development focused on reducing the size of aprepitant’s particles to a nanoscale. This therefore would increase the bioavailability of the drug.

Using this information Merck came up with a manufacturing process, (which is still used today). This nine step process includes wet milling, which reduces the particle size of the active ingredient. It also involves excipients being used to keep the nanoparticles of aprepitant separated from each other during and after the microcrystalline celluse beads being coated. This therefore prevents agglomerating of the beads, which means that nanoparticles of aprepitant remains small even after it is re dispersed from the beads.

The nine step manufacturing process involves

• A slurry of aprepitant, hydorxypropyl and water being produced
• The slurry undergoing pre-milling
• An aqueous sucrose dispersion being added to the slurry
• The slurry undergoing media-milling which produces a colloidal dispersion
• An aqueous sucrose dispersion being added to the slurry
• The microcrystalline cellulose beads being spray coated with the colloidal dispersion.
• The coated beads being sieved
• The coated microcrystalline cellulose beads are blende with micronised sodium lauryl
• The blended beads are encapsulated

The end result of the nine step process is a capsule, known as Emend, which contain aprepitant. The capsule also contains several other substances, which includes sucrose, hydroxypropyl cellulose, microcrystalline cellulose, sodium lauryl sulphate, gelatine, shellac, black iron oxide and titanium dioxide.

Mechanism of action

Aprepitant is classified as an NK1 antagonist which is because it blocks signals given off by NK1 receptors. This therefore decreases the likelihood of a patient experiencing nausea vomiting. Emend is usually taken as a preventative for CINV, which is a serious side effect experienced by over 80% of patients who undergo chemotherapy and take the drug cisplatin.

NK1 is a G protein coupled receptor and is located in the central nervous system and the peripheral nervous system. This receptor has a dominant ligand known as Substance P (SP). SP is a neuropeptide, comprising of 11 amino acids, which sends and receives impulses and messages from the brain. It is found in high concentrations in the vomiting center of the brain and when activated it results in a vomiting reflux occurring. In addition to this it also plays a key part in the transmission of pain impulses from the peripheral receptors to the central nervous system.

Cisplatin is a platinum based substance which is used primarily in chemotherapy, a common treatment for various types of cancer. While it is relatively effective, it causes numerous side effects on the patient. One of these side effects is that activates SP in the vomiting center, which results in the patient experiencing vomiting reflux.

Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic such as cisplatin by blocking substance P landing on receptors in the brains neurons. This has been proven by Positron Emission Tomography (PET) studies which have demonstrated that aprepitant can penetrate the brain and NK1 receptors in the brain. It has also been shown to increases the activity of the 5-HT3 receptor antagonists ondansetron and the corticosteroid dexamethasone, which are also used to prevent CINV caused by chemotherapy.

Aprepitant is taken orally and in the form of a capsule. Its average bioavailability is around 60-65% and has a main function of increasing the patient's plasma radioactivity and concentration, which occurs because it is more than 95% bound to plasma proteins. It is estimated that after about four hours after administration the average plasma concentration reaches it highest point. Despite this however, an increase in plasma radioactivity can last for up to 72 hours. Aprepitant is primarily eliminated from the body through metabolism, with an average of around 86% of the radioactivity being recovery through patience’s faeces.

The main chemical reactions that occurs in the body is related to the phase I metabolism of the triazolone ring of aprepitant (see figure 1). It is currently believed that the metabolism of aprepitant takes two hydrolysis steps which results in an instantaneous decarboxylation. This leads to an amide derivative forming, which is then hydrolysed further and a carboxylic acid is formed. This product (M8) then binds with the patient’s plasma to increase its radioactivity.

One of the fundamental features of aprepitant, and a major advantage it has over other chemotherapy induced side effect treatments, is it that while it successfully antagonises the NK1 receptors it has very little affinity over other receptors such as serotonin, dopamine and corticosteroid. It is estimated that aprepitant is at least 3000 times more selective of NK1 receptors compared to these other enzyme transporter, ion channels.

Other uses

Merck & Co. conducted clinical trials on aprepitant as a treatment of major depressive disorder, and received negative results.^[1] The company has since abandoned plans to market aprepitant as an antidepressant.

Notes and references