Description
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]
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].
Definition
ChEBI: 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+).
Synthesis
At 50 and 250 rpm, rolapitant, polyethylene glycol 15-hydroxystearate, refined soybean oil and medium-chain triglyceride were heated and stirred for 25 minutes to produce the oil phase; then phosphoric acid, sodium chloride and Porloxam 188 with water for injection were stirred and mixed for 20 minutes at room temperature with 350 rpm to produce the aqueous phase; the aqueous phase was added to the oil phase and homogenized for 1 minute with a high speed of 25000 rpm to produce the crude emulsion, and then homogenized for 6 times with a high pressure microfluidizer. Subsequently, the aqueous phase was added to the oil phase and homogenized at high speed for 1 minute at 25000 rpm to produce crude emulsion, and then homogenized at high pressure for 6 times with a high-pressure microfluidizer to produce rolapitant emulsion injection.
in vivo
Rolapitant (0.03-1 mg/kg for PO, 0.3-1 mg/kg for IV; single dosage) attenuates the GR-73632-induced foot-tapping response in Mongolian Gerbils[1].
Rolapitant (0.03-1 mg/kg; PO; single dosage; observed for 72 h) blocks acute emesis induced by both apomorphine and cisplatin in ferrets[1].
| Animal Model: | Female Mongolian Gerbils (30-60 g; anesthetized by inhalation of an oxygen:isofluorane mixture after 4 h PO or immediately after IV, then injected with 5 μl of 3 pmol solution of GR-73632 via ICV)[1] |
| Dosage: | 0.03, 0.1, 0.3 and 1 mg/kg for PO, 0.3 and 1 mg/kg for IV |
| Administration: | PO or IV, single dosage |
| Result: | Attenuated dose-dependently the GR-73632-induced foot-tapping response when administered PO 4 h before testing, with an ID90 of 0.3 mg/kg, and the inhibition in foot tapping for at least 24 h.
Blocked dose-dependently the foot tapping induced by GR-73632 when administered IV, with complete blockade observed at 1 mg/kg. |
| Animal Model: | Ferrets (treated with subcutaneous administration of 0.125 mg/kg apomorphine or intraperitoneal administration of 10 mg/kg cisplatin)[1] |
| Dosage: | 0.03, 0.1, 0.3 and 1 mg/kg |
| Administration: | PO; single dosage; observed for 72 h |
| Result: | Blocked dose-dependently acute emesis induced by both apomorphine and cisplatin in ferrets.
Produced a robust decrease in retches and vomits in ferrets that was maintained throughout the 72 h observation period. |
IC 50
human NK1: 0.66 nM (Ki); gerbil NK1: 0.13 nM (Ki); guinea pig NK1: 0.72 nM (Ki); monkey NK1: 2.5 nM (Ki); rabbit NK1: 31.7 nM (Ki); rat NK1: 78.6 nM (Ki); mouse NK1: 60.4 nM (Ki)
References
[1] Duffy RA, et al. Rolapitant (SCH 619734): a potent, selective and orally active neurokininNK1 receptor antagonist with centrally-mediated antiemetic effects inferrets. Pharmacol Biochem Behav. 2012 Jul;102(1):95-100. DOI:
10.1016/j.pbb.2012.03.021[2] Rapoport B, et al. Study of rolapitant, a novel, long-acting, NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). Support Care Cancer. 2015 Nov;23(11):3281-8. DOI:
10.1007/s00520-015-2738-1[3] SARAH M GLASS. Rolapitant Is a Reversible Inhibitor of CYP2D6.[J]. Drug Metabolism and Disposition, 2019, 47 6: 567-573. DOI:10.1124/dmd.118.085928.
