GNE0877

Biological Activity

GNE0877 is a highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitor with an IC50 of 3 nM. IC50 value: 3 nM Target: LRRK2 Invitrogen kinase-selectivity profiling(188 kinases) of aminopyrazole GNE0877 at 0.1 μM (145-fold overLRRK2 Ki) resulted in only four kinases showing greater than 50% inhibition (Aurora B = 51%, RSK2 = 52%, RSK4 = 62%, and RSK3 = 68%) and suggested that GNE0877 is a highly selective LRRK2 inhibitor. Furthermore, GNE0877 possessed a 212-fold biochemical-selectivity index over TTK (Ki= 150 nM), which was previously highlighted as an off-target kinase of concern because of the suggested role of TTK in the maintenance of chromosomal stability. The in vivo rat clearance for inhibitor GNE0877 was within 2-fold of measured in vitro stability, and good oral bioavailability (88%) was achieved at 50 mg/kg following administration of a methylcellulose/tween (MCT) suspension.

Chemical Information

Molecular Weight	339.32
CAS Number	1374828-69-9
Solubility (25°C)	DMSO 150 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Noeen Malik, et al. Eur J Med Chem. Development and biological evaluation of[ 18 F]FMN3PA & [ 18 F]FMN3PU for leucine-rich repeat kinase 2 (LRRK2) in vivo PET imaging

[2] Isadora Marques Paiva, et al. Prog Neuropsychopharmacol Biol Psychiatry. Inhibition of Lrrk2 reduces ethanol preference in a model of acute exposure in zebrafish

[3] Anthony A Estrada, et al. J Med Chem. Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors