In vitro and in vivo pharmacological characterization of Pronetupitant, a prodrug of the neurokinin 1 receptor antagonist Netupitant

tThe aim of the present study was to investigate the pharmacological activity of Pronetupitant, a novelcompound designed to act as prodrug of the NK1antagonist Netupitant. In receptor binding experi-ments Pronetupitant displayed high selectivity for the NK1receptor. In a calcium mobilization assayperformed on CHONK1cells Pronetupitant (100 nM, 15 min preincubation) behaved as an NK1antago-nist more potent than Netupitant (pKB8.72 and 7.54, respectively). In the guinea pig ileum bioassayPronetupitant antagonized the contractile effect of SP showing a similar potency as Netupitant (pKB≈ 9).Similar results were obtained with 5 min preincubation time while at 2 min only Pronetupitant pro-duced significant effects. In vivo in mice the intrathecal injection of 0.1 nmol SP elicited the typicalscratching, biting and licking (SBL) nociceptive response. This effect of SP was dose dependently(0.1–10 mg/kg) antagonized by Pronetupitant given intravenously 2 h before the peptide. Superimpo-sable results were obtained using Netupitant. Pharmacokinetic studies performed in rats demonstratethat Pronetupitant, after i.v. administration, is quickly (few minutes) and completely converted toNetupitant. Collectively the present results indicated that Pronetupitant acts in vitro as selective NK1antagonist more potent than Netupitant. However based on the short half-life measured for Pronetupi-tant in rats, the in vivo action of Pronetupitant can be entirely interpreted as due to its conversion to Netupitant.