title: The novel NK1 receptor antagonist MK-0869 (L-754,030) and its water soluble phosphoryl prodrug, L-758,298, inhibit acute and delayed cisplatin-induced emesis in ferrets.
abstract: The anti-emetic profile of the novel brain penetrant tachykinin NK1 receptor antagonist MK-0869 (L-754,030) 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluor o)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine and its water soluble prodrug, L-758,298, has been examined against emesis induced by cisplatin in ferrets. In a 4 h observation period, MK-0869 and L-758,298 (3 mg/kg i.v. or p.o.) inhibited the emetic response to cisplatin (10 mg/kg i.v.). The anti-emetic protection afforded by MK-0869 (0.1 mg/kg i.v.) was enhanced by combined treatment with either dexamethasone (20 mg/kg i.v.) or the 5-HT3 receptor antagonist ondansetron (0.1 mg/kg i.v.). In a model of acute and delayed emesis, ferrets were dosed with cisplatin (5 mg/kg i.p.) and the retching and vomiting response recorded for 72 h. Pretreatment with MK-0869 (4-16 mg/kg p.o.) dose-dependently inhibited the emetic response to cisplatin. Once daily treatment with MK-0869 (2 and 4 mg/kg p.o.) completely prevented retching and vomiting in all ferrets tested. Further when daily dosing began at 24 h after cisplatin injection, when the acute phase of emesis had already become established, MK-0869 (4 mg/kg p.o. at 24 and 48 h after cisplatin) prevented retching and vomiting in three out of four ferrets. These data show that MK-0869 and its prodrug, L-758,298, have good activity against cisplatin-induced emesis in ferrets and provided a basis for the clinical testing of these agents for the treatment of emesis associated with cancer chemotherapy.
authors.affiliation: Department of Pharmacology, Merck, Sharp and Dohme, Neuroscience Research Centre, Harlow, Essex, UK. david_tattersall@merck.com
authors.forename: F D
authors.initials: FD
authors.lastname: Tattersall
authors.forename: W
authors.initials: W
authors.lastname: Rycroft
authors.forename: M
authors.initials: M
authors.lastname: Cumberbatch
authors.forename: G
authors.initials: G
authors.lastname: Mason
authors.forename: S
authors.initials: S
authors.lastname: Tye
authors.forename: D J
authors.initials: DJ
authors.lastname: Williamson
authors.forename: J J
authors.initials: JJ
authors.lastname: Hale
authors.forename: S G
authors.initials: SG
authors.lastname: Mills
authors.forename: P E
authors.initials: PE
authors.lastname: Finke
authors.forename: M
authors.initials: M
authors.lastname: MacCoss
authors.forename: S
authors.initials: S
authors.lastname: Sadowski
authors.forename: E
authors.initials: E
authors.lastname: Ber
authors.forename: M
authors.initials: M
authors.lastname: Cascieri
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: D E
authors.initials: DE
authors.lastname: MacIntyre
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
mesh_terms: D000080:Acetals / Q000494:pharmacology*; D000208:Acute Disease; D000818:Animals; D000932:Antiemetics / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077608:Aprepitant; D016466:CHO Cells; D019556:COS Cells; D002945:Cisplatin / Q000633:toxicity*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D006801:Humans; D008297:Male; D009025:Morpholines / Q000378:metabolism / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012995:Solubility; D014839:Vomiting / Q000188:drug therapy*
chemical_list: D000080:Acetals; D000932:Antiemetics; D000970:Antineoplastic Agents; C400262:L 758298; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D011355:Prodrugs; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant; D002945:Cisplatin