Aprepitant

Absorption

The mean absolute oral bioavailability of aprepitant is approximately 60 to 65%.

Description

Aprepitant is an antiemetic chemical compound that belongs to “substance P” antagonists (SPA) with its effect being blocking the neurokinin 1(Nk1) receptor. It is used for the prevention of acute and delayedchemotherapy-induced nausea and vomiting(CINV) and for prevention ofpostoperative nausea and vomiting. It can also be used for the treatment of cyclic vomiting syndrome and late-stage chemotherapy induced vomiting occurring during cancer treatment. Aprepitant alleviates the case of vomiting in patients through balking the signals released by Nk1 receptors. Nk1 is a G-protein-coupled receptor with its ligand being substance P (SP). The high concentration of SP is required for the vomiting reflex. Aprepitant blocks the process of SP-NK1 signaling in activating the vomiting reflex.

Chemical properties

Off-White to Light Yellow Cyrstalline Solid

Originator

Merck (US)

The Uses of Aprepitant

A novel selective neurokinin-1 (NK-1) receptor antagonist. In vitro studies using human liver microsomes indicate that Aprepitant is metabolised primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19, and no metabolism by CYP2D6, CYP2C9, or CYP2E1. Antiemetic.

The Uses of Aprepitant

anticholinergic

What are the applications of Application

Aprepitant is a selective neurokinin-1 (NK-1) receptor antagonist

Indications

For the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including high-dose cisplatin (in combination with other antiemetic agents).

Background

Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV).

Definition

ChEBI: A morpholine-based antiemetic, which is or the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/ eurokinin 1 (NK1) receptors.

brand name

Emend (Merck).

Pharmacokinetics

Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CI NV).

Clinical Use

Aprepitant, a substance P (neurokinin-1 [NK-1]) receptor antagonist used for the treatment of chemotherapy-induced nausea and vomiting, was launched in the US and was later approved in the European Union. It is a non-peptide analog having a trisubstituted morpholine with three chiral centers. Two syntheses have been described. In six steps p-fluorophenylacetic acid is converted to 4-benzyl-3-pfluorophenyl- 2-oxomorpholine with a resolution step setting the S-stereochemistry. This intermediate is converted in six steps to aprepitant, with two of the steps utilizing a chiral induction strategy to set the new centers based upon the chiral 2- oxomorpholine intermediate. SAR efforts leading to aprepitant included engineering in potency for NK-1, decreasing affinity for L-type calcium ion channels, most importantly by decreasing the basicity of the core heterocycle. In vitro, it binds with very high affinity (90 pM) to the hNK1 in transfected CHO cells. It is described as an inverse agonist of hNK-1 receptor, with slow dissociation rate under some conditions. In ferrets dosed orally or intravenously prior to emetogen challenge (cisplatin, apomorphine or morphine), retching and vomiting was reduced. Its antiemetic effect is enhanced with the dosing of dexamethasone and it is effective against both the acute and delayed phase of cisplatin-induced emesis. Cisplatin-induced emesis clinical studies showed that aprepitant (125 mg p.o.) in combination with ondansetron (32 mg i.v.) and dexamethasone (20 mg p.o.) therapeutically followed by repeat dosing (days 2–5) of aprepitant (80 mg) dexamethasone (20 mg) provided acute (8 h) and delayed phase (days 2–7) no vomiting rates of 83 and 70%, respectively. L-758298, a prodrug of aprepitant, was not as effective as ondansetron (32 mg i.v.) in reducing acute phase vomiting, but was superior in reducing vomiting in the delayed phase. The terminal half-life range of aprepitant is 9–13 h and the bioavailability is about 65%. It is highly protein bound (95%) and has a Vdss of 70 L. It is a moderate CYP3A4 inhibitor, thus several drugs cleared by CYP3A4 should not be used concurrently. It is also an inducer of CYP2C9 thus potentially modulating the PK of drugs cleared by CYP2C9. Most side effects were mild to moderate, with fatigue, asthenia, diarrhea, and hiccups.

Synthesis

Several variations to the synthesis of aprepitant (II) have been published by the Merck group. The latest optimized synthesis utilizing a novel crystallization-induced diastereoselective synthesis of aprepitant is highlighted in the Scheme. The synthetic approach entailed (1) the synthesis and coupling of the key pieces, N-benzyl lactam lactol 13 and sec-phenethyl alcohol 7, to provide lactam acetal 14, (2) stereoselective elaboration to the key intermediate 14, and (3) conversion to the final compound via either intramolecular cyclization or intermolecular coupling with triazolinone chloride 24. The intermediate secphenethyl alcohol 7 was synthesized in 97% yield and 95% e.e. (improved to 99% e.e. after recrystallization) via the enantioselective borane reduction of ketone 6 in the presence of 2 mol % of (S)-oxazaborolidine catalyst 8. The optimized conditions involved the slow addition of ketone 6 to a solution containing catalyst 8 and BH3?¤PhNEt2 complex in MTBE at ¨C10 to 0??C. The synthesis of lactam 12 was done by reacting N-benzylethanolamine (9) with slight excess of aqueous glyoxylic acid (10, 2.3 equivalent of 50% aqueous solution) in refluxing THF. Adjustment of the solvent composition from predominantly THF to predominantly water resulted in the crystallization of lactam 12 directly from 11 in the reaction mixture in 76% yield. Lactam 12 was treated with trifluoroacetic anhydride (1 equiv) to give trifluoroacetate 13, which was reacted in situ with chiral alcohol 7 in the presence of BF3?¤OEt2 to give, after workup, a 55:45 mixture of the acetals 14 and 15 in 95-98% overall yield. To obtain the desired diastereomer from the 55:45 mixture of 14 and 15, an optimized crystallization sequence was developed. To a solution of the crude mixture in heptane, 3,7-dimethyl-3-octanol (17) (0.9 equiv) was added, cooled to ¨C10 to ¨C5??C and, after seeding the mixture with pure 14, potassium salt of 3,7-dimethyl-3-octanol (16) (0.3 equiv) was added to initiate the crystallization-induced epimerization of 15 to 14. After 5 hr, the mixture was transformed into a 96:4 mixture from which 14 was isolated in 83-85% yield and ￡?99% e.e. Under an optimized condition, the lactam 1 4 was reacted with 4- fluorophenylmagnesium bromide (18) (1.3 equiv) in THF at ambient temperature followed by methanol quench and addition of p-toluenesulfonic acid (1.8-2.2 equiv). Immediate hydrogenation of this mixture in the presence of 5% Pd/C gave the addition product 19, which was isolated as hydrochloride salt in 91% yield. Under these conditions, no cleavage of the benzylic ether group was seen, even after extended hydrogenation periods. Elaboration to aprepitant (II) was done by the initial alkylation of 19 in the presence of a base with amidrazone chloride 20, which was prepared from chloroacetonitrile, to give the intermediate 21. Thermolysis of 21 in toluene provided aprepitant (II) in 85% overall yield. Alternatively, the hydrochloride salt 19 has also been alkylated directly with the triazolinone chloride 24 to give aprepitant (II).

Drug interactions

Potentially hazardous interactions with other drugs
Antidepressants: avoid with St John’s wort.
Antipsychotics: avoid with pimozide.
Avanafil: possibly increases avanafil concentration.
Cytotoxics: possibly increases bosutinib concentration - avoid or reduce bosutinib dose; possibly increases ibrutinib concentration - reduce ibrutinib dose.
Oestrogens and progestogens: may cause contraceptive failure.
Ulipristal: possibly reduces contraceptive effect - avoid.

Metabolism

Aprepitant primarily undergoes CYP3A4-mediated metabolism, as well as minor metabolism mediated by CYP1A2 and CYP2C19. About seven metabolites of aprepitant have been identified in human plasma, which all retain weak pharmacological activity.

Metabolism

Aprepitant undergoes extensive metabolism. Following a single IV 100mg dose of [14C]fosaprepitant, a prodrug for aprepitant, aprepitant accounts for approximately 19% of the radioactivity in plasma over 72 hours. 12 metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant, primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19, occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active.
Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine (57%) and via biliary excretion in faeces (45%).

storage

Store at -20°C

References

Curran, Monique P., and D. M. Robinson. "Aprepitant."Drugs69.13(2009):1853-1878.
Sant P. Chawla M.D. † ‡, et al. "Establishing the dose of the oral NK 1, antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting." Cancer 97.9(2003):2290-2300.
Warr, D. G., et al. "Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy." Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology23.12(2005):2822-30.
https://en.wikipedia.org/wiki/Aprepitant