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

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...

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Bibliographic Details
Published in:Pharmacology, biochemistry and behavior biochemistry and behavior, 2012-07, Vol.102 (1), p.95-100
Main Authors: Duffy, Ruth A., Morgan, Cynthia, Naylor, Robert, Higgins, Guy A., Varty, Geoffrey B., Lachowicz, Jean E., Parker, Eric M.
Format: Article
Language:English
Subjects:
Administration, Oral
Animal models
Animals
Antiemetics
Antiemetics - administration & dosage
Antiemetics - chemistry
Antiemetics - metabolism
Calcium efflux
Central nervous system
Cercopithecus aethiops
Chemotherapy-induced nausea and vomiting (CINV)
CHO Cells
COS Cells
Cricetinae
Data processing
Dogs
Female
Ferret: emesis
Ferrets
Foot
Gerbillinae
Guinea Pigs
Humans
Intravenous administration
Macaca fascicularis
Mice
Mustela
Neurokinin NK1
Neurokinin NK1 receptors
Neurokinin-1 Receptor Antagonists
NK1 antagonist
Oral administration
Post-operative nausea and vomiting (POVN)
Protein Binding - physiology
Rabbits
Rats
Receptors, Neurokinin-1 - metabolism
Spiro Compounds - administration & dosage
Spiro Compounds - chemistry
Spiro Compounds - metabolism
Vomiting
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Summary: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 0.1mg/kg. Rolapitant was active at 0.1 and 1mg/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. ►Rolapitant (SCH 619734) is a high affinity, selective, neurokinin NK1 functional antagonist. ►SCH 619734 penetrates the central nervous system following oral administration. ►SCH 619734 dose-dependently inhibits NK1 receptor-mediated foot tapping in gerbils. ►Rolapitant reverses both apomorphine and cisplatin-induced emesis in ferrets.
ISSN:0091-3057
1873-5177
DOI:10.1016/j.pbb.2012.03.021