Aprepitant
[CAS 170729-80-3]

Identification

• Classification: API >> Digestive system medication >> Antiemetic emetic
• Name: Aprepitant
• Synonyms: 5-[2(R)-[1(R)-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazol-3-one
• Molecular Formula: C₂₃H₂₁F₇N₄O₃
• Molecular Weight: 534.43
• CAS Registry Number: 170729-80-3 (221350-96-5)
• EC Number: 677-636-6
• SMILES: C[C@H](C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)O[C@@H]2[C@@H](N(CCO2)CC3=NNC(=O)N3)C4=CC=C(C=C4)F

Properties

• Density: 1.5$+/-$0.1 g/cm³ Calc.^*
• Solubility: DMSO 56 mg/ml, Water $lessThan$1 mg/m (Expl.)
• Index of refraction: 1.564 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07;GHS08;GHS09 Warning
• Risk Statements: H319-H351-H373-H410
• Safety Statements: P203-P260-P264+P265-P273-P280-P305+P351+P338-P318-P319-P337+P317-P391-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410
Carcinogenicity	Carc.	2	H351
Eye irritation	Eye Irrit.	2	H319
Acute toxicity	Acute Tox.	4	H302
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2A	H319
Skin irritation	Skin Irrit.	2	H315
Acute toxicity	Acute Tox.	4	H332
Serious eye damage	Eye Dam.	1	H318
Acute toxicity	Acute Tox.	4	H312
Carcinogenicity	Carc.	1B	H350

Discovery and Applications

Aprepitant is a small-molecule drug that acts as a selective antagonist of the neurokinin-1 (NK1) receptor. It is used primarily as an antiemetic to prevent acute and delayed nausea and vomiting associated with chemotherapy, as well as postoperative nausea and vomiting. Its therapeutic action is based on blocking the binding of substance P, a neuropeptide involved in emetic signaling pathways in the central nervous system.

The discovery of aprepitant is closely linked to research on the role of substance P in emesis. Substance P was identified as a key neurotransmitter in the brainstem regions that regulate the vomiting reflex, particularly in the area postrema and nucleus tractus solitarius. These findings led to the hypothesis that blocking NK1 receptors, which are the primary receptors for substance P, could provide effective antiemetic therapy.

Aprepitant was developed as part of a medicinal chemistry effort to design potent and orally active NK1 receptor antagonists. Early peptide-based NK1 antagonists showed biological activity but lacked suitable pharmacokinetic properties for clinical use. Structural optimization led to non-peptide small molecules with improved oral bioavailability, metabolic stability, and central nervous system penetration. Aprepitant emerged from this development process as a clinically effective candidate.

Structurally, aprepitant contains a triazolinone core linked to substituted aromatic rings and chiral centers that contribute to its high affinity and selectivity for the NK1 receptor. The molecular design allows it to fit into the receptor’s binding pocket, preventing substance P from activating the receptor. This inhibition disrupts the signaling cascade that triggers nausea and vomiting.

Mechanistically, aprepitant acts as a competitive antagonist at NK1 receptors located in both central and peripheral nervous system pathways involved in emesis. Chemotherapy and other emetogenic stimuli can increase the release of substance P, leading to activation of NK1 receptors in the brainstem. By blocking these receptors, aprepitant reduces both acute and delayed phases of chemotherapy-induced nausea and vomiting, complementing other antiemetic agents that target serotonin (5-HT3) or dopamine receptors.

Aprepitant is administered orally and is often used in combination with other antiemetic drugs such as corticosteroids and 5-HT3 receptor antagonists. This combination approach reflects the multifactorial nature of chemotherapy-induced emesis, which involves multiple neurotransmitter systems. Aprepitant is particularly effective in controlling delayed nausea and vomiting, which are less responsive to serotonin receptor antagonists alone.

The pharmacokinetics of aprepitant involve good oral absorption and extensive hepatic metabolism, primarily through cytochrome P450 3A4 (CYP3A4). It also acts as a moderate inhibitor of CYP3A4, which can lead to clinically relevant drug–drug interactions. The compound has a relatively long half-life, allowing once-daily dosing over a short treatment course.

Clinically, aprepitant has significantly improved the management of chemotherapy-induced nausea and vomiting since its introduction. It is especially important in regimens involving highly emetogenic chemotherapeutic agents, where control of vomiting is critical for patient quality of life and treatment adherence. Its use has been incorporated into standard antiemetic guidelines in oncology.

Adverse effects of aprepitant are generally mild and may include fatigue, hiccups, constipation, and mild gastrointestinal disturbances. These effects are usually manageable and are outweighed by its clinical benefits in preventing severe nausea and vomiting.

Overall, aprepitant is a neurokinin-1 receptor antagonist developed through targeted drug design based on the role of substance P in emesis. Its discovery represents an important advance in supportive cancer care, providing effective control of chemotherapy-induced nausea and vomiting through a novel mechanism distinct from earlier antiemetic therapies.

References

2026. Aprepitant increases the antitumor activity of chemotherapy by chemosensitizing breast cancer cells. Cancer and Metastasis Reviews.
DOI: 10.1007/s10555-026-10315-4

2026. Advantages of a standardized PONV prophylaxis : The consistent implementation significantly reduces the incidence of postoperative nausea and vomiting and the need for antiemetic rescue medication. Die Anaesthesiologie.
DOI: 10.1007/s00101-026-01646-6

2026. A randomized, double-blind, placebo-controlled trial of olanzapine versus placebo plus ondansetron and dexamethasone for antiemetic prophylaxis in patients receiving oxaliplatin-, irinotecan-, or carboplatin-based chemotherapy. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer.
DOI: 10.1007/s00520-026-10490-8