Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets.
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Duffy RA, Morgan C, Naylor R, Higgins GA, Varty GB, Lachowicz JE, Parker EM
Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets.
Pharmacol Biochem Behav. 2012 Jul;102(1):95-100. doi: 10.1016/j.pbb.2012.03.021. Epub 2012 Mar 31.
- PubMed ID
- 22497992 [ View in PubMed]
- Abstract
NK1 receptor antagonists have been shown to have a variety of physiological and potential therapeutic effects in animal models and in humans. The present studies demonstrate that Rolapitant (SCH 619734, (5S)-8(S)-[[1(R)-[3,5 bis(trifluoromethyl)phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4,5]decan-2-one ) is a selective, bioavailable, CNS penetrant neurokinin NK1 receptor antagonist that shows behavioral effects in animals models of emesis. In vitro studies indicate that rolapitant has a high affinity for the human NK1 receptor of 0.66 nM and high selectivity over the human NK2 and NK3 subtypes of >1000-fold, as well as preferential affinity for human, guinea pig, gerbil and monkey NK1 receptors over rat, mouse and rabbit. Rolapitant is a functionally competitive antagonist, as measured by calcium efflux, with a calculated Kb of 0.17 nM. Rolapitant reversed NK1 agonist-induced foot tapping in gerbils following both intravenous and oral administration up to 24 hours at a minimal effective dose (MED) of 0.1 mg/kg. Rolapitant was active at 0.1 and 1 mg/kg in both acute and delayed emesis models in ferrets, respectively, consistent with clinical data for other NK1 antagonists. Clinical efficacy of anti-emetics is highly correlated with efficacy in the ferret emesis model, suggesting rolapitant is a viable clinical candidate for this indication.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Rolapitant Neurokinin 1 receptor Protein Humans YesAntagonistDetails