Aprepitant

Aprepitant (Emend (US, EU)) is an antiemetic chemical compound that belongs to a class of drugs called substance P antagonists (SPA). It mediates its effect by blocking the neurokinin 1 (NK1) 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.

On January 2008, the FDA approved fosaprepitant, an intravenous form of aprepitant, which is to be sold under the tradename Emend Injection in the US and as Ivemend in some other countries.

Initial development
Acute or delayed CINV is an unpleasant side effect experienced by over 80% of patients undergoing initial and repeated highly emetogenic cancer chemotherapy, for example cisplatin. Throughout the 1990s a noticeable increase occurred in the number of diagnosed cancer patients undergoing chemotherapy and therefore experiencing CINV. As a result of this, toward the end of the decade, initial research was conducted to try to develop a drug that eases the severity and decreases 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 vomiting. This is due to the receptor binding with substance P, a peptide neurotransmitter.

Structure and properties of aprepitant
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.

Aprepitant is an off-white crystalline solid that 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, researchers discovered that aprepitant is effective in prevention. 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 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 in 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 streamlined 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, hydroxypropyl cellulose, and water being produced
 * The slurry undergoing pre-milling
 * An aqueous sucrose dispersion being added to the slurry
 * The slurry undergoing media-milling that 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 blended with micronised sodium lauryl sulfate
 * 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 sulfate, gelatin, shellac, black iron oxide and titanium dioxide.

Mechanism of action
Aprepitant is classified as an NK1 antagonist because it blocks signals given off by NK1 receptors. This, therefore, decreases the likelihood of vomiting in patients. Emend is usually taken as a preventative for CINV, which is a serious side-effect experienced by over 80% of patients who undergo chemotherapy.

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, composed 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.

Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs 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 increase the activity of the 5-HT3 receptor antagonists ondansetron and the corticosteroid dexamethasone, which are also used to prevent nausea and vomiting caused by chemotherapy.

Aprepitant is taken orally in the form of a capsule. Before clinical testing, a new class of therapeutic agent has to be characterized in terms of preclinical metabolism and excretion studies. Average bioavailability is found to be around 60-65%. Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of coadministered medicinal products that are metabolized through CYP3A4. Following IV administration of a 14C-labelled prodrug of aprepitant (L-758298), which is converted rapidly and completely to aprepitant, approximately 57% of the total radioactivity is excreted in the urine and 45% in faeces. No unchanged substance is excreted in urine.

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. The company has since abandoned plans to market aprepitant as an antidepressant.