LRRK2-IN-14 (Compound 8) is an orally active LRRK2 inhibitor. LRRK2-IN-14 has an IC50 of 6.3 nM for LRRK2(G2019S) cell activity.LRRK2-IN-14 has an inhibitory effect on hERG (IC50=22 μM). LRRK2-IN-14 has blood-brain barrier permeability[1].
in vivo
LRRK2-IN-14 (30 mg/kg; p.o.; single dose) inhibits phosphorylation of G2019S mutant LRRK2 in the brain in ICR mice[1].
Pharmacokinetic Analysis in ICR mice[1]
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 (%)
i.v.
5
4101
/
/
0.905
1233
16.3
5122
5181
1.27
/
p.o.
5
/
2803
0.083
0.709
/
/
3657
3672
1.22
70.9
brain
5
/
837
0.292
0.648
/
/
1230
1233
1.14
/
Animal Model:
ICR mice[1]
Dosage:
30 mg/kg
Administration:
p.o.; single dose
Result:
Reduced phosphorylated LRRK2 levels to 34%.
References
[1] Kim K, et al. Concurrent Optimizations of Efficacy and Blood-Brain Barrier Permeability in New Macrocyclic LRRK2 Inhibitors for Potential Parkinson's Disease Therapeutics. J Med Chem. 2024 May 9;67(9):7647-7662. DOI:10.1021/acs.jmedchem.4c00520
