APREPITANT

Aprepitant is a marketed potent NK1 inhibitor (IC50 = 0.1 nM, human) with good selectivity against NK2 (IC50 = 4.5 µM, human) and NK3 (IC50 = 300 nM, human) determined in a Substance P displacement assay in CHO cells. Ferret and rat NK1 IC50 values were reported to be 0.7 nM and 4 nM respectively. In addition, high selectivity versus several serotonin receptors, L-type calcium channel and monoamine oxidase was reported. Additional selectivity data of aprepitant in a full GPCR panel would further increase the confidence in aprepitant as a selective chemical probe for the NK1 receptor. Aprepitant dose-dependently inhibited substance P-induced IP1 synthesis in hNK1/CHO cells. In vivo PK data is available for several species (ferret, rat, dog). Efficacy was demonstrated in several anti-emetic in vivo models in ferrets.

Aprepitant is a potent NK-1 antagonist (IC50 = 0.09 nM) with good selectivity against NK-2 (>10,000-fold) and NK-3 (>1,000-fold) determined by displacement of 125I-labelled ligands in CHO cells. Good selectivity was also reported against a panel of ~60 GPCRs and ion channels. Dose-dependent inhibition of SP-induced IP1 synthesis was observed in CHO cells. Good exposure is seen following intravenous dosing in rats and dogs. Intravenous administration in gerbils at 0.04 mg/kg reversed the effects of a NK-1 agonist GR 73632. Although there is no direct oral pharmacokinetic data available, 3.0 mg/kg oral dosing in ferrets induced up to 50-fold higher antiemetic action versus the control.