Rolapitant hydrochloride

Rolapitant (SCH619734) hydrochloride is a potent, selective, long-acting and orally active neurokinin 1 (NK1) receptor antagonist with a Ki of 0.66 nM. Rolapitant hydrochloride does not interact with CYP3A4. Rolapitant hydrochloride shows potent anti-emetic activity in a ferret emesis model[1][2].

Signaling Pathways >> Neuronal Signaling >> Neurokinin Receptor

Research Areas >> Neurological Disease

Signaling Pathways >> GPCR/G Protein >> Neurokinin Receptor

human NK1:0.66 (Ki)

gerbil NK1:0.13 (Ki)

guinea pig NK1:0.72 (Ki)

monkey NK1:2.5 (Ki)

rabbit NK1:31.7 (Ki)

rat NK1:78.6 (Ki)

mouse NK1:60.4 (Ki)

Rolapitant has high selectivity over the human NK2 and NK3 subtypes of more than 1000-fold, as well as preferential affinity for human, guinea pig, gerbil and monkey NK1 receptors over rat, mouse and rabbit[1]. Rolapitant (1-1000 nM) inhibits the GR-73632 (an NK1 receptor agonist)-induced calcium efflux with a concentration-dependent and competitive manner in CHO cells expressing the human NK1 receptor[1].

Rolapitant (0.03-1 mg/kg for PO, 0.3-1 mg/kg for IV; single dosage) attenuates the GR-73632-induced foot-tapping response in Mongolian Gerbils[1]. Rolapitant (0.03-1 mg/kg; PO; single dosage; observed for 72 h) blocks acute emesis induced by both apomorphine and cisplatin in ferrets[1]. Animal Model: Female Mongolian Gerbils (30-60 g; anesthetized by inhalation of an oxygen:isofluorane mixture after 4 h PO or immediately after IV, then injected with 5 μl of 3 pmol solution of GR-73632 via ICV)[1] Dosage: 0.03, 0.1, 0.3 and 1 mg/kg for PO, 0.3 and 1 mg/kg for IV Administration: PO or IV, single dosage Result: Attenuated dose-dependently the GR-73632-induced foot-tapping response when administered PO 4 h before testing, with an ID90 of 0.3 mg/kg, and the inhibition in foot tapping for at least 24 h. Blocked dose-dependently the foot tapping induced by GR-73632 when administered IV, with complete blockade observed at 1 mg/kg. Animal Model: Ferrets (treated with subcutaneous administration of 0.125 mg/kg apomorphine or intraperitoneal administration of 10 mg/kg cisplatin)[1] Dosage: 0.03, 0.1, 0.3 and 1 mg/kg Administration: PO; single dosage; observed for 72 h Result: Blocked dose-dependently acute emesis induced by both apomorphine and cisplatin in ferrets. Produced a robust decrease in retches and vomits in ferrets that was maintained throughout the 72 h observation period.

[1]. Duffy RA, et al. Rolapitant (SCH 619734): a potent, selective and orally active neurokininNK1 receptor antagonist with centrally-mediated antiemetic effects inferrets. Pharmacol Biochem Behav. 2012 Jul;102(1):95-100.

[2]. Rapoport B, et al. Study of rolapitant, a novel, long-acting, NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC). Support Care Cancer. 2015 Nov;23(11):3281-8.