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Netupitant

Netupitant structure

CAS No:
290297-26-6
Formula:
C30H32F6N4O
Chemical Name:
Netupitant
Synonyms:
Benzeneacetamide,N,α,α-trimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]-3,5-bis(trifluoromethyl)-;N,α,α-Trimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]-3,5-bis(trifluoromethyl)benzeneacetamide;Netupitant;Ro 67-31898/000;2-[3,5-Bis(trifluoromethyl)phenyl]-N-[6-(4-methylpiperazin-1-yl)-4-o-tolylpyridin-3-yl]-N-methylisobutyramide;2-[3,5-Bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanamide
Categories:
Pharmaceutical Intermediates > Bulk Drug Intermediates

Description

Netupitant (CID-6451149) is a highly potent and selective, orally active neurokinin-1 receptor antagonist with Ki of 0.95 nM.IC50 value: 0.95 nM (Ki) [1]Target: NK1 receptorin vitro: Netupitant also dose-dependently inhibited the SP response as expected from an NK1 receptor antagonist. Importantly, when both palonosetron and netupitant were present, they exhibited an enhanced inhibition of the SP response compared to either of the two antagonists alone [2].in vivo: In mice the intratheca

Netupitant is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of 2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoic acid with the secondary amino group of N-methyl-4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin-3-amine; an antiemetic used in combination with palonosetron hydrochloride (under the trade name Akynzeo) to treat nausea and vomiting in patients undergoing cancer chemotherapy. It has a role as an antiemetic and a neurokinin-1 receptor antagonist. It is a monocarboxylic acid amide, an organofluorine compound, an aminopyridine, a member of toluenes, a N-alkylpiperazine and a N-arylpiperazine.|Netupitant is an antiemitic drug approved by the FDA in October 2014 for use in combination with palonosetron for the prevention of acute and delayed vomiting and nausea associated with cancer chemotherapy including highly emetogenic chemotherapy. Netupitant is a neurokinin 1 receptor antagonist. The combination drug is marketed by Eisai Inc. and Helsinn Therapeutics (U.S.) Inc. under the brand Akynzeo.|Netupitant is a Substance P/Neurokinin-1 Receptor Antagonist. The mechanism of action of netupitant is as a Neurokinin 1 Antagonist, and Cytochrome P450 3A4 Inhibitor, and P-Glycoprotein Inhibitor, and Breast Cancer Resistance Protein Inhibitor.|Netupitant is a selective neurokinin 1 (NK1) receptor antagonist with potential antiemetic activity. Netupitant competitively binds to and blocks the activity of the human substance P/NK1 receptors in the central nervous system (CNS), thereby inhibiting NK1-receptor binding of the endogenous tachykinin neuropeptide substance P (SP), which may result in the prevention of chemotherapy-induced nausea and vomiting (CINV). SP is found in neurons of vagal afferent fibers innervating the brain-stem nucleus tractus solitarii and the area postrema, which contains the chemoreceptor trigger zone (CTZ), and may be elevated in response to chemotherapy. The NK-receptor is a G-protein receptor coupled to the inositol phosphate signal-transduction pathway and is found in both the nucleus tractus solitarii and the area postrema.

Netupitant Basic Attributes

Molecular Weight：

578.61

Exact Mass：

578.59

EC Number：

1308068-626-2

UNII：

7732P08TIR

DSSTox ID：

DTXSID50183271

NCI Thesaurus Code：

C96745

ATC Code：

A04AA

Characteristics

PSA：

39.7

XLogP3：

6.8

Density：

1.3±0.1 g/cm3

Melting Point：

156.2-160.0 °C

Boiling Point：

597.4°C at 760 mmHg

Flash Point：

315.1±30.1 °C

Refractive Index：

1.540

Vapor Pressure：

3.09E-14mmHg at 25°C

Toxicity

Toxicity Summary：

Daily oral administration of netupitant in rats at doses up to 30 mg/kg (1.9 times the human AUC in male rats and 3.7 times the human AUC in female rats at the recommended human dose) had no effects on fertility or reproductive performance.

Protein Binding：

> 99.5% at drug concentrations ranging from 10-1300 ng/mL.

Drug Information

Drug Indication：

Netupitant is an antiemitic drug approved by the FDA in October 2014 for use in combination with palonosetron for the prevention of acute and delayed vomiting and nausea associated with cancer chemotherapy including highly emetogenic chemotherapy.|FDA Label|Akynzeo is indicated in adults for the:Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin based cancer chemotherapy.Prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy.|Prevention of chemotherapy-induced nausea and vomiting

Absorption：

Upon oral administration of a single dose of netupitant, netupitant started to be measurable in plasma between 15 minutes and 3 hours after dosing. Plasma concentrations reached Cmax in approximately 5 hours. There was a greater than dose-proportional increase in the systemic exposure with the dose increase from 10 mg to 300 mg and a dose-proportional increase in systemic exposure with a dose increase from 300 mg to 450 mg.|Primarily fecal.|In cancer patients, Vz/F: 1982 ± 906 L (mean ± SD).|Estimated systemic clearance of 20.3 ± 9.2 L/h (mean ± SD).

Metabolism/Metabolites：

Once absorbed, netupitant is extensively metabolized to form three major metabolites: desmethyl derivative, M1; N-oxide derivative, M2; and OH-methyl derivative, M3. Metabolism is mediated primarily by CYP3A4 and to a lesser extent by CYP2C9 and CYP2D6. Metabolites M1, M2 and M3 were shown to bind to the substance P/neurokinin 1 (NK1) receptor.

Biological Half-Life：

96 hours with CV% of 61.

Mechanism of Action：

Delayed emesis (vomiting) has been largely associated with the activation of tachykinin family neurokinin 1 (NK1) receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses.

MeSH Entry Terms：

netupitant

Netupitant Use and Manufacturing

Uses

Antiemetic.

Use Classification：

Human drugs -> Akynzeo -> EMA Drug Category|Antiemetics and antinauseants -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

Computed Properties

Molecular Weight:578.6
XLogP3:6.8
Hydrogen Bond Acceptor Count:10
Rotatable Bond Count:5
Exact Mass:578.24803063
Monoisotopic Mass:578.24803063
Topological Polar Surface Area:39.7
Heavy Atom Count:41
Complexity:865
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes

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