Based on their in vitro potency and selectivity, 46 and 40 were selected for preliminary evaluation of pharmacokinetic (PK) properties in CD-1 mice over the course of five hours. Two routes of administration, intraperitoneal (IP) and oral (PO), were explored for a single dose (10 mg/kg). Importantly, no treatment-related adverse effects were observed in the animals during the exposure period. As shown in Figure , 46 demonstrated decent exposure as reflected by the AUC values (6874 and 2349 h•nM for IP and PO) but was mostly consumed over the 5-hour exposure period and had similarly short half-lives (0.55 and 1.05 h for IP and PO). Plasma concentrations of 46 remained above its cellular target engagement IC50 value for PIKfyve when dosed orally. In comparison, 40 showed low exposure after IP and PO administrations (AUC values <75 h•nM) but remained at concentrations well above its PIKfyve cellular affinity, as assessed using the PIKfyve NanoBRET assay. The extrapolated half-life (T1/2 = 13.6 h) after oral administration suggests that increasing the dose of 40 should result in high plasma concentrations of this compound over an extended dosing period.