title: 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.
authors.affiliation: Department of CV/Metabolic Diseases, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07023, United States. ruth.duffy@merck.com
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Duffy
authors.forename: Cynthia
authors.initials: C
authors.lastname: Morgan
authors.forename: Robert
authors.initials: R
authors.lastname: Naylor
authors.forename: Guy A
authors.initials: GA
authors.lastname: Higgins
authors.forename: Geoffrey B
authors.initials: GB
authors.lastname: Varty
authors.forename: Jean E
authors.initials: JE
authors.lastname: Lachowicz
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000932:Antiemetics / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004285:Dogs; D005260:Female; D005289:Ferrets; D005849:Gerbillinae; D006168:Guinea Pigs; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D064729:Neurokinin-1 Receptor Antagonists; D011485:Protein Binding / Q000502:physiology; D011817:Rabbits; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000932:Antiemetics; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D013141:Spiro Compounds; C578834:rolapitant