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

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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.

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Aprepitant: a review of its use in the prevention of nausea and vomiting.

D. Robinson, Kevin Curran (2008)

Aprepitant (Emend) is a neurokinin-1 (NK(1)) receptor antagonist that is able to alleviate the emetic effects of substance P. When combined with a standard regimen of a corticosteroid (dexamethasone) and a serotonin 5-HT(3) receptor antagonist (ondansetron), oral aprepitant (125 mg on day 1 then 80 mg once daily on days 2 and 3) was effective in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with single or multiple cycles of highly emetogenic chemotherapy (HEC). This aprepitant regimen was also effective in the prevention of CINV in patients treated with single or multiple cycles of moderately emetogenic chemotherapy (MEC). A single oral dose of aprepitant 40 mg administered prior to patients undergoing abdominal surgery was also effective in the prevention of postoperative nausea and vomiting (PONV). Aprepitant was generally well tolerated. Aprepitant is a recommended option for the treatment of PONV, and when combined with a corticosteroid and 5-HT(3) receptor antagonist is a recommended regimen for the treatment of CINV.

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The anti-emetic effects of CP-99,994 in the ferret and the dog: role of the NK1 receptor.

Steven McLean, T F Seeger, B Jereczek-Fossa … (1995)

1. The selective NK1 receptor antagonist, CP-99,994, produced dose-related (0.1-1.0 mg kg-1, s.c.) inhibition of vomiting and retching in ferrets challenged with central (loperamide and apomorphine), peripheral (CuSO4) and mixed central and peripheral (ipecac, cisplatin) emetic stimuli. 2. Parallel studies with the enantiomer, CP-100,263 (1 mg kg-1, s.c.), which is > 1,000 fold less potent as a NK1 antagonist, indicated that it was without significant effect against CuSO4, loperamide, cisplatin and apomorphine-induced emesis. Against ipecac, it inhibited both retching and vomiting, expressing approximately 1/10th the potency of CP-99,994. 3. The 5-HT3 receptor antagonist, tropisetron (1 mg kg-1, s.c.) inhibited retching and vomiting to cisplatin and ipecac, but not CuSO4 or loperamide. 4. CP-99,994 (1 mg kg-1, i.v.) blocked retching induced by electrical stimulation of the ventral abdominal vagus without affecting the cardiovascular response, the apnoeic response to central vagal stimulation or the guarding and hypertensive response to stimulation of the greater splanchnic nerves. CP-99,994 (1 mg kg-1, i.v.) did not alter baseline cardiovascular and respiratory parameters and it failed to block the characteristic heart rate, blood pressure and respiratory rate/depth changes in response to i.v. 2-methyl-5-HT challenge (von Bezold-Jarisch reflex). 5. Using in vitro autoradiography, [3H]-substance P was shown to bind to several regions of the ferret brainstem with the density of binding in the nucleus tractus solitarius being much greater than in the area postrema. This binding was displaced by CP-99,994 in a concentration-related manner. 6. In dogs, CP-99,994 (40 micrograms kg-1 bolus and 300 micrograms kg-1 h-1, i.v.) produced statistically significant reductions in vomiting to CuSO4 and apomorphine as well as retching to CuSO4. 7. Together, these studies support the hypothesis that the NK1 receptor antagonist properties of CP-99,994 are responsible for its broad spectrum anti-emetic effects. They also suggest that CP-99,994 acts within the brainstem, most probably within the nucleus tractus solitarius although the involvement of the area postrema could not be excluded.

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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.

F.D. Tattersall, W Rycroft, M Cumberbatch … (2000)

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.