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MedKoo Cat#: 200650 | Name: Casopitant mesylate
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Casopitant mesylate is the mesylate salt of a centrally-acting neurokinin 1 (NK1) receptor antagonist with antidepressant and antiemetic activities. Casopitant competitively binds to and blocks the activity of the NK1 receptor, thereby inhibiting NK1-receptor binding of the endogenous tachykinin neuropeptide substance P (SP), which may result in antiemetic effects. 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 NK1 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.

Chemical Structure

Casopitant mesylate
Casopitant mesylate
CAS#414910-30-8 (mesylate)

Theoretical Analysis

MedKoo Cat#: 200650

Name: Casopitant mesylate

CAS#: 414910-30-8 (mesylate)

Chemical Formula: C31H39F7N4O5S

Exact Mass: 0.0000

Molecular Weight: 712.72

Elemental Analysis: C, 52.24; H, 5.52; F, 18.66; N, 7.86; O, 11.22; S, 4.50

Price and Availability

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1mg USD 480.00 Ready to ship
5mg USD 850.00 2 Weeks
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Related CAS #
414910-30-8 (mesylate) 414910-27-3 (free base)
Synonym
GW679769; GW 679769; GW-679769; Casopitant mesylate. Trade names: Rezonic (US); Zunrisa (EU).
IUPAC/Chemical Name
(2R,4S)-4-(4-acetylpiperazin-1-yl)-N-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-2-(4-fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxamide methanesulfonate
InChi Key
YRFKYVWDPCOSTE-REWBLLDVSA-N
InChi Code
InChI=1S/C30H35F7N4O2.CH4O3S/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;1-5(2,3)4/h5-6,13-16,19,25,27H,7-12,17H2,1-4H3;1H3,(H,2,3,4)/t19-,25+,27-;/m1./s1
SMILES Code
O=C(N(C)[C@H](C)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1)N2[C@H](C[C@H](CC2)N3CCN(CC3)C(C)=O)C4=CC=C(C=C4C)F.CS(=O)(O)=O
Appearance
Solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>5 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.03.00
More Info
Related: 414910-27-3 (Casopitant free base) 414910-30-8 (Casopitant mesylate). Casopitant (trade names Rezonic (US), Zunrisa (EU)) is an neurokinin 1 (NK1) receptor antagonist undergoing research for the treatment of chemotherapy-induced nausea and vomiting (CINV).  It is currently under development by GlaxoSmithKline (GSK). In July 2008, the company filed a marketing authorisation application with the European Medicines Agency. The application was withdrawn in September 2009 because GSK decided that further safety assessment was necessary. (see: http://en.wikipedia.org/wiki/Casopitant).    
Product Data
Product Data
Certificate of Analysis
View CoA: current batch, Lot#A20M10C14
Safety Data Sheet (SDS)
View Safety Data Sheet (SDS)
Instruction
View handling instruction
Biological target:
Casopitant mesylate (GW679769B) is a potent, selective, brain permeable and orally active neurokinin 1 (NK1) receptor antagonist.
In vitro activity:
A similar, but less potent, pattern of CYP3A4 enzyme induction was observed in hepatocyte cultures treated with casopitant, especially in cells from donors 2 and 3, the ones who had responded more markedly to RIF. The slight decrease in the CYP3A4 activity observed at 20 μM compared with that at 5 μM may be due to the fact that casopitant and its metabolite are also inhibitors/inactivators of CYP3A4. Cytotoxicity of casopitant at this concentration was not likely, as this decrease was not observed for the other P450 activities tested on the same human hepatocyte preparations (data not shown). The ability of casopitant and its metabolite GSK525060 to inhibit CYP3A4 metabolism of probe substrates (MID and NIF), in a direct and metabolism-dependent manner, was investigated in pooled HLM, and the results are summarized in Table 3. Both casopitant and GSK525060 were shown to inhibit CYP3A4 activity, as measured with both probe substrates, with an IC50 lower than 10 μM. Moreover, the preincubation of casopitant or its metabolite with HLM in the presence of NADPH did increase their inhibitory effects, suggesting that both drugs also behaved as metabolism-dependent inhibitors of CYP3A4. In particular, the decreases in IC50 for casopitant and GSK525060 in the metabolism of MID were characterized by IC50 shifts of approximately 4.3- and 3.0-fold, respectively. Reference: Drug Metab Dispos. 2011 Mar;39(3):363-72. http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=21149541
In vivo activity:
Coadministration of casopitant with the CYP3A4 inducer RIF resulted in decreased plasma concentrations of both casopitant and GSK525060. After daily dosing with RIF, casopitant exposure (after a single dose of 150 mg) was greatly decreased with AUC(0–t), and Cmax was reduced by 96% (ratio = 0.039) and 89% (ratio = 0.11), respectively (Table 6). Likewise, systemic exposure to GSK525060 as AUC(0–t) (after casopitant and RIF coadministration) was decreased by 94% (ratio = 0.057), whereas tmax of both casopitant and GSK525060 was not affected by the presence of RIF. Reference: Drug Metab Dispos. 2011 Mar;39(3):363-72. http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=21149541

Preparing Stock Solutions

The following data is based on the product molecular weight 712.72 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol:
1. Motta P, Pons N, Pagliarusco S, Pellegatti M, Bonomo F. Casopitant: in vitro data and SimCyp simulation to predict in vivo metabolic interactions involving cytochrome P450 3A4. Drug Metab Dispos. 2011 Mar;39(3):363-72. doi: 10.1124/dmd.110.035071. Epub 2010 Dec 13. PMID: 21149541.
In vivo protocol:
1. Motta P, Pons N, Pagliarusco S, Pellegatti M, Bonomo F. Casopitant: in vitro data and SimCyp simulation to predict in vivo metabolic interactions involving cytochrome P450 3A4. Drug Metab Dispos. 2011 Mar;39(3):363-72. doi: 10.1124/dmd.110.035071. Epub 2010 Dec 13. PMID: 21149541. 2. Minthorn E, Mencken T, King AG, Shu A, Rominger D, Gontarek RR, Han C, Bambal R, Davis CB. Pharmacokinetics and brain penetration of casopitant, a potent and selective neurokinin-1 receptor antagonist, in the ferret. Drug Metab Dispos. 2008 Sep;36(9):1846-52. doi: 10.1124/dmd.108.021758. Epub 2008 Jun 12. PMID: 18556439.
1: Tubog TD, Kane TD. Pharmacological Strategies for Postdischarge Nausea and Vomiting: Evidence-based Review Update. J Perianesth Nurs. 2024 Dec 20:S1089-9472(24)00462-3. doi: 10.1016/j.jopan.2024.09.010. Epub ahead of print. PMID: 39708024. 2: Soltani A, Hashemy SI. Homology modeling, virtual screening, molecular docking, and ADME approaches to identify a potent agent targeting NK2R protein. Biotechnol Appl Biochem. 2024 Feb;71(1):213-222. doi: 10.1002/bab.2533. Epub 2023 Oct 30. PMID: 37904319. 3: Sakurai H, Yonezawa K, Tani H, Mimura M, Bauer M, Uchida H. Novel Antidepressants in the Pipeline (Phase II and III): A Systematic Review of the US Clinical Trials Registry. Pharmacopsychiatry. 2022 Jul;55(4):193-202. doi: 10.1055/a-1714-9097. Epub 2022 Jan 19. PMID: 35045580; PMCID: PMC9259184. 4: Piechotta V, Adams A, Haque M, Scheckel B, Kreuzberger N, Monsef I, Jordan K, Kuhr K, Skoetz N. Antiemetics for adults for prevention of nausea and vomiting caused by moderately or highly emetogenic chemotherapy: a network meta-analysis. Cochrane Database Syst Rev. 2021 Nov 16;11(11):CD012775. doi: 10.1002/14651858.CD012775.pub2. PMID: 34784425; PMCID: PMC8594936. 5: Weibel S, Rücker G, Eberhart LH, Pace NL, Hartl HM, Jordan OL, Mayer D, Riemer M, Schaefer MS, Raj D, Backhaus I, Helf A, Schlesinger T, Kienbaum P, Kranke P. Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: a network meta-analysis. Cochrane Database Syst Rev. 2020 Oct 19;10(10):CD012859. doi: 10.1002/14651858.CD012859.pub2. PMID: 33075160; PMCID: PMC8094506. 6: Zhang Z, Zhang Y, Chen G, Hong S, Yang Y, Fang W, Luo F, Chen X, Ma Y, Zhao Y, Zhan J, Xue C, Hou X, Zhou T, Ma S, Gao F, Huang Y, Chen L, Zhou N, Zhao H, Zhang L. Olanzapine-Based Triple Regimens Versus Neurokinin-1 Receptor Antagonist-Based Triple Regimens in Preventing Chemotherapy-Induced Nausea and Vomiting Associated with Highly Emetogenic Chemotherapy: A Network Meta- Analysis. Oncologist. 2018 May;23(5):603-616. doi: 10.1634/theoncologist.2017-0378. Epub 2018 Jan 12. PMID: 29330211; PMCID: PMC5947448. 7: Abdel-Rahman O. Neurokinin-1 inhibitors in the prevention of nausea and vomiting from highly emetogenic chemotherapy: a network meta-analysis. Ther Adv Med Oncol. 2016 Sep;8(5):396-406. doi: 10.1177/1758834016654902. Epub 2016 Jun 29. PMID: 27583032; PMCID: PMC4981292. 8: van der Vorst MJ, Neefjes EC, Konings IR, Verheul HM. Prophylactic treatment for delayed chemotherapy-induced nausea and vomiting after non-AC based moderately emetogenic chemotherapy: a systematic review of randomized controlled trials. Support Care Cancer. 2015 Aug;23(8):2499-506. doi: 10.1007/s00520-015-2778-6. Epub 2015 Jun 4. PMID: 26041480; PMCID: PMC4483187. 9: Melton MS, Nielsen KC, Tucker M, Klein SM, Gan TJ. Long-acting serotonin antagonist (Palonosetron) and the NK-1 receptor antagonists: does extended duration of action improve efficacy? Anesthesiol Clin. 2014 Jun;32(2):505-16. doi: 10.1016/j.anclin.2014.02.004. Epub 2014 Apr 18. PMID: 24882134. 10: Adams LM, Johnson B, Murray S. A pharmacokinetic, pharmacodynamic, and safety study of intravenous cyclophosphamide with an oral casopitant antiemetic regimen in cancer patients. Clin Pharmacol Drug Dev. 2014 Mar;3(2):93-100. doi: 10.1002/cpdd.57. Epub 2013 Sep 25. PMID: 27128454. 11: Trist DG, Ratti E, Bye A. Why receptor reserve matters for neurokinin1 (NK1) receptor antagonists. J Recept Signal Transduct Res. 2013 Dec;33(6):333-7. doi: 10.3109/10799893.2013.843194. Epub 2013 Oct 9. PMID: 24106886. 12: Di Fabio R, Alvaro G, Braggio S, Carletti R, Gerrard PA, Griffante C, Marchioro C, Pozzan A, Melotto S, Poffe A, Piccoli L, Ratti E, Tranquillini E, Trower M, Spada S, Corsi M. Identification, biological characterization and pharmacophoric analysis of a new potent and selective NK1 receptor antagonist clinical candidate. Bioorg Med Chem. 2013 Nov 1;21(21):6264-73. doi: 10.1016/j.bmc.2013.09.001. Epub 2013 Sep 11. PMID: 24075145. 13: Muñoz M, Coveñas R. Safety of neurokinin-1 receptor antagonists. Expert Opin Drug Saf. 2013 Sep;12(5):673-85. doi: 10.1517/14740338.2013.804059. Epub 2013 May 25. PMID: 23706125. 14: dos Santos LV, Souza FH, Brunetto AT, Sasse AD, da Silveira Nogueira Lima JP. Neurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomiting: a systematic review. J Natl Cancer Inst. 2012 Sep 5;104(17):1280-92. doi: 10.1093/jnci/djs335. Epub 2012 Aug 21. PMID: 22911671. 15: Ziejewski MK, Solomon HM, Stanislaus D, Clark RL, White TE, Apostoli AR. The potential role for corticosterone in the induction of cleft palate in mice after treatment with a selective NK-1 receptor antagonist, casopitant (GW679769B). Birth Defects Res B Dev Reprod Toxicol. 2012 Feb;95(1):54-62. doi: 10.1002/bdrb.20341. Epub 2011 Nov 29. PMID: 22127931. 16: Ratti E, Bellew K, Bettica P, Bryson H, Zamuner S, Archer G, Squassante L, Bye A, Trist D, Krishnan KR, Fernandes S. Results from 2 randomized, double- blind, placebo-controlled studies of the novel NK1 receptor antagonist casopitant in patients with major depressive disorder. J Clin Psychopharmacol. 2011 Dec;31(6):727-33. doi: 10.1097/JCP.0b013e31823608ca. Erratum in: J Clin Psychopharmacol. 2012 Apr;32(2):185. PMID: 22020354. 17: Zamuner S, Rabiner EA, Fernandes SA, Bani M, Gunn RN, Gomeni R, Ratti E, Cunningham VJ. A pharmacokinetic PET study of NK₁ receptor occupancy. Eur J Nucl Med Mol Imaging. 2012 Feb;39(2):226-35. doi: 10.1007/s00259-011-1954-2. Epub 2011 Oct 13. PMID: 21993526. 18: Crivellente F, Tontodonati M, Fasdelli N, Casartelli A, Dorigatti R, Faustinelli I, Cristofori P. NT-proBNP as a biomarker for the assessment of a potential cardiovascular drug-induced liability in beagle dogs. Cell Biol Toxicol. 2011 Dec;27(6):425-38. doi: 10.1007/s10565-011-9197-3. Epub 2011 Aug 8. PMID: 21823034. 19: Hesketh PJ, Wright O, Rosati G, Russo M, Levin J, Lane S, Moiseyenko V, Dube P, Kopp M, Makhson A. Single-dose intravenous casopitant in combination with ondansetron and dexamethasone for the prevention of oxaliplatin-induced nausea and vomiting: a multicenter, randomized, double-blind, active-controlled, two arm, parallel group study. Support Care Cancer. 2012 Jul;20(7):1471-8. doi: 10.1007/s00520-011-1235-4. Epub 2011 Aug 7. PMID: 21822913. 20: Casartelli A, Lanzoni A, Comelli R, Crivellente F, Defazio R, Dorigatti R, Fasdelli N, Faustinelli I, Pagliarusco S, Tontodonati M, Cristofori P. A novel and integrated approach for the identification and characterization of drug- induced cardiac toxicity in the dog. Toxicol Pathol. 2011 Feb;39(2):361-71. doi: 10.1177/0192623310390704. Epub 2010 Dec 14. PMID: 21422262.