CASOPITANT

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C30H35F7N4O2
Molecular Weight	616.6133
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@@H](N(C)C(=O)N1CC[C@@H](C[C@@H]1C2=C(C)C=C(F)C=C2)N3CCN(CC3)C(C)=O)C4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F

InChI

InChIKey=XGGTZCKQRWXCHW-WMTVXVAQSA-N

InChI=1S/C30H35F7N4O2/c1-18-13-24(31)5-6-26(18)27-17-25(40-11-9-39(10-12-40)20(3)42)7-8-41(27)28(43)38(4)19(2)21-14-22(29(32,33)34)16-23(15-21)30(35,36)37/h5-6,13-16,19,25,27H,7-12,17H2,1-4H3/t19-,25+,27-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24106886 | http://www.fiercebiotech.com/biotech/glaxosmithkline-announces-new-drug-application-and-phase-iii-results-for-rezonic-zunrisa
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/19445564 | http://adisinsight.springer.com/drugs/800018590

Casopitant (GW679769) is a novel substituted piperidine derivative that competitively binds with NK1 receptors. The full occupancy of the receptor by their piperidine compound inhibits its binding with tachykinin neurotransmitters, including SP. Casopitant, in a series of in vitro and in vivo experimentations, has exhibited a potent NK1 receptor antagonism. On 29 May 2008, GlaxoSmithKline announced the submission of a new drug application to the FDA for intravenous and oral formulations of casopitant mesylate. This drug was proposed for the prevention of chemotherapy-induced nausea and vomiting as an add-on therapy to the standard dual therapy of 5-HT3 receptor antagonists + dexamethasone. The submission also included a proposed indication for postoperative nausea and vomiting prevention. Rezonic™ is the proposed trade name for casopitant mesylate in the United States; Zunrisa™ is the proposed trade name for casopitant mesylate for GlaxoSmithKline’s global group of companies. In September 2009, GlaxoSmithKline decided to discontinue all regulatory filings for casopitant based on an estimate of the amount of additional safety data.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Neurokinin 1 receptor 35 Target ID: CHEMBL249 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24106886	Antagonist 2778		10.2 null [pKi]
Cytochrome P450 3A4 127 Target ID: CHEMBL340 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21149541	Inhibitor 8297		9.86 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Postoperative nausea and vomiting 29 Sources: http://adisinsight.springer.com/drugs/800018590 https://clinicaltrials.gov/ct2/show/NCT00334152	Palliative		Phase III 656	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis.	2006 Apr 1	18632487
(S)-1-[3,5-Bis-(trifluoro-meth-yl)phen-yl]-N-methylethyl-amine-(R)-2-hydroxy-butane-dioic acid (1/1).	2008 Dec 24	21581651
Pharmacokinetics and brain penetration of casopitant, a potent and selective neurokinin-1 receptor antagonist, in the ferret.	2008 Sep	18556439
Pharmacological management of chemotherapy-induced nausea and vomiting: focus on recent developments.	2009	19368415
Casopitant: a novel NK(1)-receptor antagonist in the prevention of chemotherapy-induced nausea and vomiting.	2009 Apr	19536319
Disposition and metabolism of radiolabeled casopitant in humans.	2009 Aug	19420128
Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled trial.	2009 Jun	19428297
Randomized, double-blind, dose-ranging trial of the oral neurokinin-1 receptor antagonist casopitant mesylate for the prevention of cisplatin-induced nausea and vomiting.	2009 Nov	19541792
Impact of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of ondansetron and dexamethasone.	2009 Sep	19205755
Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron.	2009 Sep	19205754
Ketoconazole and rifampin significantly affect the pharmacokinetics, but not the safety or QTc interval, of casopitant, a neurokinin-1 receptor antagonist.	2010 Aug	20124517
Phase II study to evaluate the safety and efficacy of the oral neurokinin-1 receptor antagonist casopitant (GW679769) administered with ondansetron for the prevention of postoperative and postdischarge nausea and vomiting in high-risk patients.	2010 Jul	20526194
Winning a won game: caffeine panacea for obesity syndemic.	2010 Jun	21119886
Determination of casopitant and its three major metabolites in dog and rat plasma by positive ion liquid chromatography/tandem mass spectrometry.	2010 Nov 1	20870467
Management of chemotherapy-induced nausea and vomiting.	2010 Sep-Oct	21128556
A novel and integrated approach for the identification and characterization of drug-induced cardiac toxicity in the dog.	2011 Feb	21422262
Discovery and biological characterization of (2R,4S)-1'-acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4'-bipiperidine-1-carboxamide as a new potent and selective neurokinin 1 (NK1) receptor antagonist clinical candidate.	2011 Feb 24	21229983
Why receptor reserve matters for neurokinin1 (NK1) receptor antagonists.	2013 Dec	24106886

Patents

Sample Use Guides

In Vivo Use Guide

A single 100 or 150 mg dose schedule of casopitant, orally or intravenously

Route of Administration: Other

In Vitro Use Guide

Casopitant inhibited CYP3A4 activity in human liver microsomes with an IC50 lower than 10 uM.

Name

Type

Language

CASOPITANT

Official Name

English

CASOPITANT [MART.]

Common Name

English

casopitant [INN]

Common Name

English

GW679769

Code

English

Casopitant [WHO-DD]

Common Name

English

GW-679769

Code

English

Classification Tree Code System Code

WHO-VATC

QA04AD13