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Rolapitant

Rolapitant structure

CAS No:
552292-08-7
Formula:
C25H26F6N2O2
Chemical Name:
Rolapitant
Synonyms:
Rolapitant;(5S,8S)-8-(((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one hydrochloride.;Rolapitant(sch619734);(5S,8S)-8-[[[(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl]oxy]methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one;(5S,8S)-8-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethoxy}methyl)-8-phenyl-1,7-diazaspiro[4.5]decan-2-one;1,7-Diazaspiro[4.5]decan-2-one,8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-,(5S,8S)-;(5S,8S)-8-[[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,9-diazaspiro[4.5]decan-2-one;SCH619734
Categories:
Active Pharmaceutical Ingredients > Nervous System Drugs

Description

Rolapitant is an azaspiro compound that is 1,7-diazaspiro[4.5]decan-2-one carrying additional phenyl and 1-{[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl substituents at position 8. Used (in the form of the hydrochloride hydrate) for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy. It has a role as an antiemetic and a neurokinin-1 receptor antagonist. It is an ether, an azaspiro compound, a member of pyrrolidin-2-ones, a member of piperidines and an organofluorine compound. It is a conjugate base of a rolapitant(1+).|Rolapitant is a potent, highly selective, long-acting Neurokinin-1 (NK-1) receptor antagonist approved for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in adults. Delayed-phase CINV typically occurs >24 hours after chemotherapy treatment and is principally mediated by Neurokinin-1 and its ligand Substance P, which is released in the gut following chemotherapy administration. Neurokinin-1 is also known as Tachykinin Receptor 1 (TACR1), Neurokinin 1 Receptor (NK1R), and Substance P Receptor (SPR). By blocking Substance P from interacting with NK-1 receptors in the gut and the central nervous system, rolapitant prevents late-phase CINV. Unlike other available NK-1 receptor antagonists, rolapitant is not an inhibitor of Cytochrome P450 enzyme CYP3A4 and has a long elimination half-life, allowing a single dose to prevent both acute and late-phase CINV during the first 120 hours post-chemotherapy.|Rolapitant is a Substance P/Neurokinin-1 Receptor Antagonist. The mechanism of action of rolapitant is as a Neurokinin 1 Antagonist, and Cytochrome P450 2D6 Inhibitor, and Breast Cancer Resistance Protein Inhibitor, and P-Glycoprotein Inhibitor.|Rolapitant is an orally available antiemetic agent that is used to prevent cancer chemotherapy related nausea and vomiting. Rolapitant therapy has not been associated with serum enzyme elevations or with instances of clinically apparent liver injury with jaundice.

Rolapitant [5S,8S)-8-[[(1R)-1-[3,5 bis(trifluoromethyl phenyl] ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one] is a highaffinity NK1 receptor antagonist recently approved under the name Varubi as a treatment for nausea and vomiting caused by chemotherapy by the U.S. Food and Drug Administration (FDA). Rolapitant is metabolized in vivo primarily by CYP3A4 to form the major metabolite M19.[3]

Rolapitant Basic Attributes

Molecular Weight：

500.48

Exact Mass：

500.48

EC Number：

812-147-5

UNII：

NLE429IZUC

DSSTox ID：

DTXSID90203740

Color/Form：

White to off-white

ATC Code：

A04AD|A - Alimentary tract and metabolism

Characteristics

Density：

1.34±0.1 g/cm3(Predicted)

Boiling Point：

523.5±50.0 °C(Predicted)

PKA：

15.88±0.40(Predicted)

Critical Temperature & Pressure：

Store at -20°C

Safety Information

GHS Classification：

|Warning|H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]|P201, P202, P281, P308+P313, P405, and P501|Aggregated GHS information provided by 2 companies from 2 notifications to the ECHA C&L Inventory.

Toxicity

Toxicity Summary：

Most common adverse reactions occurring in >3% of patients receiving moderately emetogenic chemotherapy and combinations of anthracycline and cyclophosphamide included decreased appetite, neutropenia, dizziness, dyspepsia, urinary tract infection, stomatitis, and anemia. Most common adverse reactions occurring in patients receiving cisplatin-based highly emetogenic chemotherapy included neutropenia, hiccups, and abdominal pain.

Hepatotoxicity：

Serum aminotransferase elevations following initial cycles of chemotherapy occurred in

Protein Binding：

Rolapitant is 99.8% bound to human plasma protein.

Drug Information

Drug Indication：

This drug is indicated in adults in combination with other antiemetics for the prevention of delayed nausea and vomiting associated with emetogenic chemotherapy.|FDA Label|Prevention of delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults.Varuby is given as part of combination therapy.|Prevention of nausea and vomiting|Drug: Rolapitanthydrochloride

LiverTox Summary：

Rolapitant is an orally available antiemetic agent that is used to prevent cancer chemotherapy related nausea and vomiting. Rolapitant therapy has not been associated with serum enzyme elevations or with instances of clinically apparent liver injury with jaundice.

MeSH：

Compounds that inhibit or block the activity of NEUROKININ-1 RECEPTORS. (See all compounds classified as Neurokinin-1 Receptor Antagonists.)

Absorption：

Following administration of rolapitant, plasma concentrations reached peak levels in about 4 hours.|Rolapitant was found to be 14.2% renally excreted and 73% fecally excreted. Of the fecally excreted compounds|460 L|0.96 L/hour

Metabolism/Metabolites：

Rolapitant is metabolized primarily by Cytochrome P450 enzyme 3A4 (CYP3A4) to its major active and circulating metabolite M19 (C4-pyrrolidine-hydroxylated rolapitant).

Biological Half-Life：

Mean terminal half life ranged from 169 to 183 hours (~7 days).

Mechanism of Action：

Rolapitant is an orally active, highly selective Neurokinin-1 Receptor (NK1R) antagonist. NK1 receptors are located primarily in the gut and central nervous system and are activated by Substance P following chemotherapy administration. By binding to the NK1 receptor, rolapitant prevents binding of its ligand Substance P, which is released in the gut following chemotherapy administration.

MeSH Entry Terms：

(5S,8S)-8-(((1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)methyl)-8-phenyl-1,7-diazaspiro(4.5)decan-2-one

Rolapitant Use and Manufacturing

Uses

Rolapitant (SCH619734) is a potent, selective, long-acting and orally active neurokinin 1 (NK1) receptor antagonist with a Ki of 0.66 nM. Rolapitant does not interact with CYP3A4. Rolapitant shows potent anti-emetic activity in a ferret emesis model[1][2].

Use Classification：

Human drugs -> Varuby -> 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

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Rolapitant cas 552292-08-7

CAS No.: 552292-08-7

Grade: Analytical Reagent

Content: 99%

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