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 NK 1 receptor antagonist MK–0869 (L–754,030) 2–(R)–(1–(R)–(3,5–bis(trifluoromethyl)phenylethoxy)–3–(S)–(4–fluoro)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–HT 3 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.