LRRK2-IN-14 (Compound 8), an orally active inhibitor of LRRK2, exhibits an IC 50 of 6.3 nM against LRRK2(G2019S) cell activity and demonstrates inhibitory effects on hERG with an IC 50 of 22 μM. Additionally, LRRK2-IN-14 is permeable to the blood-brain barrier [1].

LRRK2-IN-14 (1 μM; 30 min) demonstrates high metabolic stability in liver microsomes, with a stability rate of 79.3% [1].

In ICR mice, a single oral dose of LRRK2-IN-14 (30 mg/kg) successfully inhibited the phosphorylation of the G2019S mutation of LRRK2 in the brain [1]. Pharmacokinetic analyses conducted in these mice revealed the following parameters: Route Dose (mg/kg) C0 (ng/mL) Cmax (ng/mL) Tmax (h) t1/2 (h) Vdss (mL/kg) Clobs (mL/min/kg) AUC0-last (ng·h/mL) AUC0-INF (ng·h/mL) MRT0-INF (h) F (%) with intravenous administration at 5 mg/kg showing 4101 ng/mL initial concentration, and oral administration at the same dosage yielding a max concentration of 2803 ng/mL at approximately 0.083 hours. The half-life for oral administration was noted as 0.709 hours. The brain concentration peaked at 837 ng/mL, with a time to peak of 0.292 hours and a half-life of 0.648 hours, achieving an AUC0-last and AUC0-INF of 1230 and 1233 ng·h/mL respectively [1]. In this animal model, using ICR mice, the single-dose oral administration reduced phosphorylated LRRK2 levels to 34%.