Rolapitant

Description: Rolapitant (formerly known as SCH619734) is a potent, selective, CNS penetrant and orally bioactive neurokinin NK1 receptor antagonist with a Ki of 0.66 nM. NK1 receptor antagonists have been shown to have a variety of physiological and potential therapeutic effects in animal models and in humans. Rolapitant 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.

References: Pharmacol Biochem Behav. 2012 Jul; 102(1):95-100.