GNE-0877 (GNE 0877; GNE0877) is a novel, highly potent and selective leucine-rich repeat kinase 2 (LRRK2) inhibitor with important biological activity. It inhibits LRRK2 with a Ki of 0.7 nM. GNE-0877 showed significantly enhanced LRRK2 cellular potency (3 nM) and low turnover in human liver microsomes and hepatocytes with no evidence of glucuronidation. Invitrogen kinase-selectivity profiling (188 kinases) of GNE-0877 at 0.1 μM resulted in only four kinases showing greater than 50% inhibition and suggested that GNE-0877 is a highly selective LRRK2 inhibitor. Furthermore, GNE-0877 possessed a 212-fold biochemical-selectivity index over TTK (Ki = 150 nM).

Physicochemical Properties

Molecular Formula	C14H16N7F3
Molecular Weight	339.31894
Exact Mass	339.141
CAS #	1374828-69-9
PubChem CID	69093374
Appearance	White to yellow solid powder
Density	1.4±0.1 g/cm3
Boiling Point	506.3±60.0 °C at 760 mmHg
Flash Point	260.0±32.9 °C
Vapour Pressure	0.0±1.3 mmHg at 25°C
Index of Refraction	1.584
LogP	1.51
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	4
Heavy Atom Count	24
Complexity	487
Defined Atom Stereocenter Count	0
InChi Key	ZPPUMAMZIMPJGP-UHFFFAOYSA-N
InChi Code	InChI=1S/C14H16F3N7/c1-8-10(6-24(23-8)13(2,3)7-18)21-12-20-5-9(14(15,16)17)11(19-4)22-12/h5-6H,1-4H3,(H2,19,20,21,22)
Chemical Name	2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile .
Synonyms	GNE 0877; GNE-0877; GNE0877;
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	GNE0877 (1 μM; 10–30 min) exhibits good hepatocyte and human liver microsome cellular potency[1].
ln Vivo	The LRRK2 Ser1292 autophosphorylation is inhibited by GNE0877 (10 and 50 mg/kg; ip once)[1].
Cell Assay	Cell Viability Assay[1] Cell Types: Human liver microsomes and hepatocytes Tested Concentrations: 1 μM Incubation Duration: 10, 20 and 30 min Experimental Results: Exibited low turnover and good in vitro stability in human liver microsomes and hepatocytes with no glucuronidation.
Animal Protocol	Animal/Disease Models: BAC transgenic mice expressing human LRRK2 protein with the G2019S Parkinson's disease mutation[1] Doses: 10 and 50 mg/kg Route of Administration: intraperitoneal (ip)injection; 10 and 50 mg/kg once Experimental Results: Tration-dependently inhibited Ser1292 autophosphorylation with an IC50 of 3 nM.
References	[1]. Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem. 2014 Feb 13;57(3):921-36.

Solubility Data

Solubility (In Vitro)

DMSO : ~250 mg/mL (~736.77 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.13 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.13 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.9471 mL	14.7354 mL	29.4707 mL
	5 mM	0.5894 mL	2.9471 mL	5.8941 mL
	10 mM	0.2947 mL	1.4735 mL	2.9471 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.