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Rolapitant (SCH 619734): a potent, selective and orally active neurokinin NK1 receptor antagonist with centrally-mediated antiemetic effects in ferrets.

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.
AuthorsRuth A Duffy, Cynthia Morgan, Robert Naylor, Guy A Higgins, Geoffrey B Varty, Jean E Lachowicz, Eric M Parker
JournalPharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 102 Issue 1 Pg. 95-100 (Jul 2012) ISSN: 1873-5177 [Electronic] United States
PMID22497992 (Publication Type: Journal Article)
CopyrightCopyright © 2012 Elsevier Inc. All rights reserved.
Chemical References
  • Antiemetics
  • Neurokinin-1 Receptor Antagonists
  • Receptors, Neurokinin-1
  • Spiro Compounds
  • rolapitant
Topics
  • Administration, Oral
  • Animals
  • Antiemetics (administration & dosage, chemistry, metabolism)
  • CHO Cells
  • COS Cells
  • Chlorocebus aethiops
  • Cricetinae
  • Dogs
  • Female
  • Ferrets
  • Gerbillinae
  • Guinea Pigs
  • Humans
  • Macaca fascicularis
  • Mice
  • Neurokinin-1 Receptor Antagonists
  • Protein Binding (physiology)
  • Rabbits
  • Rats
  • Receptors, Neurokinin-1 (metabolism)
  • Spiro Compounds (administration & dosage, chemistry, metabolism)

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