Aprepitant

Structure and properties

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. It has three chiral centres very close together, which combine to produce an amino acetal arrangement. Its empirical formula 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 reasonably 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 byproducts such as methane and magnesium chloride. The environmental concerns of the synthesis of aprepitant became so great that Merck research team decided 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 being joined to a racemic morpholine precursor. 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 being attached to the morpholine ring. Once this has been achieved the third and final step can initiated. This step involved a side chain of triazolinone being added to the ring. Once this step has been successfully completed a stable molecule of aprepitant has been produced.

This more streamlined route yields around 76% more aprepitant than the original process and reduces the operating cost by a significant amount. In addition, the new process also reduces the amount of solvent and reagents required by about 80% and saving an estimated 340,000L per ton of aprepitant produced.

The improvements in the synthesis process have also resulted in a decrease in the number long-term detrimental to the natural environment, due to elimination of hazardous chemicals from the procedure of this technique

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.

NK₁ is a G protein-coupled receptor located in the central and 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 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 reflex. 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 brain's neurons. Positron emission tomography (PET) studies, have demonstrated that aprepitant can cross the blood brain barrier and bind to NK₁ receptors in the human 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 co-administered medicinal products that are metabolized through CYP3A4. Specific interaction has been demonstrated with oxycodone, where aprepitant both increased the efficacy and worsened the side effects of oxycodone; however it is unclear whether this is due to CPY3A4 inhibition or through its NK-1 antagonist action. Following IV administration of a ¹⁴C-labeled 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 feces. No unchanged substance is excreted in urine.

One of the main features of aprepitant, and a major advantage it has over other chemotherapy-induced side-effect treatments, is its ability to selectively antagonize NK₁ receptors, while having very low affinity to other common receptors such as serotonin, dopamine, and corticosteroid. It is estimated that aprepitant is at least 3,000 times more selective to NK₁ receptors compared to these other enzyme transporter, ion channels. The normal dosing of aprepitant given as 125 mg in the first day after chemotherapy and followed by 80 mg the following 2 days.

Major Depression

Encouraged by positive results in their early controlled studies of aprepitant (300 mg/d with enforced food intake) and L-759,274(another NK₁ receptor antagonist), as well as those of CP-122,721 (Pfizer) in patients with major depressive disorder, Merck & Co. conducted Phase III clinical trials on aprepitant in which patients received 80 mg or 160 mg/d (a new formulation, prescribed without enforced food intake) as a treatment for major depressive disorder. Despite achieving 90-95% receptor occupancy of aprepitant in certain brain regions, negative clinical results were observed in three actively controlled studies. The company has since abandoned plans to market aprepitant 160 mg as an antidepressant. Subsequently, large clinically positive double blind controlled studies with two additional NK₁ receptor antagonists, casopitant, and orvepitant (both GlaxoSmithKine compounds) have been published in peer reviewed medical journals. This work now replicates the early findings of Merck and Co with aprepitant and L-759,274, and of Pfizer with CP-122,721. Arguably, the weight of preclinical data and unambiguous positive clinical evidence (in over 2000 patients studied in five well-controlled RCTs, of five separate compounds [three tested at 2 or more dose levels] conducted by three independent labs) provides critical evidence that NK₁ receptor antagonism, including that of aprepitant, is an authentically distinct antidepressant mechanism. Across all these studies, efficacy appeared to be dose-related. Only mild, transient, and tolerable side effects, not those typically observed with either the SSRI, SNRI, or NRI classes of antidepressants, have been observed.

Beyond suggestions that PET receptor occupancy must not be used routinely to cap dosing for new medical indications for this class, or that > 99% human receptor occupancy might be required for consistent psycho-pharmacological or other therapeutic effects, critical scientific dissection and debate of the above data might be needed to enable aprepitant, and the class of NK₁ antagonists as a whole, to fulfill preclinically predicted utilities beyond CINV (i.e., for other psychiatric disorders, addictions, neuropathic pain, migraine, osteoarthritis, overactive bladder, inflammatory bowel disease, and other disorders with suspected inflammatory or immunological components (see anti-cancer below.) However, most data remain proprietary and thus reviews on the expanded clinical potential for drugs like aprepitant range from optimistic to crepe-hanging.