GNE-7915 (GNE 7915; GNE7915) is a novel, highly potent, selective, and brain-penetrant leucine-rich repeat kinase 2 (LRRK2) inhibitor with anti-PD (Parkinson's disease) activity. It inhibits LRRK2 with an IC50 and a Ki of 9 nM and 1 nM, respectively. GEN-7915 has been shown to induce dephosphorylation of LRRK2 in the brain of transgenic mice. GNE-7915 is not reported to cause cellular or genetic toxicity, and has progressed into preclinical studies in cynomolgus monkeys. Inhibition of LRRK2 kinase activity has neuroprotective benefits, and provides a means of addressing the underlying biochemical cause of Parkinson's disease for the first time.

Physicochemical Properties

Molecular Formula	C19H21F4N5O3
Molecular Weight	443.40
Exact Mass	443.158
CAS #	1351761-44-8
Related CAS #	GNE-7915 tosylate;2070015-00-6
PubChem CID	58539171
Appearance	Off-white to light yellow solid powder
Density	1.4±0.1 g/cm3
Boiling Point	629.9±65.0 °C at 760 mmHg
Flash Point	334.7±34.3 °C
Vapour Pressure	0.0±1.8 mmHg at 25°C
Index of Refraction	1.578
LogP	1.81
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	6
Heavy Atom Count	31
Complexity	593
Defined Atom Stereocenter Count	0
InChi Key	XCFLWTZSJYBCPF-UHFFFAOYSA-N
InChi Code	InChI=1S/C19H21F4N5O3/c1-3-24-16-12(19(21,22)23)10-25-18(27-16)26-14-9-13(20)11(8-15(14)30-2)17(29)28-4-6-31-7-5-28/h8-10H,3-7H2,1-2H3,(H2,24,25,26,27)
Chemical Name	(4-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone
Synonyms	GNE 7915; GNE-7915; GNE7915;
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	For GNE-7915 and compound 19, single-digit nanomolar LRRK2 cell activity was obtained by keeping the methoxy/fluoro arrangement at C-2'/C-5' and varying the aminoalkyl R1 substitutions. Only TTK demonstrated more than 50% inhibition when the Invitrogen kinase assay was expanded to include 0.1 μM (187 kinases) of GNE-7915 (100-fold LRRK2 Ki) and 19 (250-fold LRRK2 Ki). At 0.1 μM, a selectivity analysis of GNE-7915 was conducted utilizing the DiscoverX KinomeScan55 competitive binding assay panel, which comprises 392 distinct kinases. Probe-shift binding was observed at >50% for 10 kinases and >65% exclusively for LRRK2, TTK, and ALK, thereby corroborating GNE-7915's exceptional selectivity for LRRK2. GNE-7915 and 19 only inhibited 5-HT2B, with >70% inhibition at 10 μM, according to cerep receptor analysis (including extended brain panel). In vitro functional tests have demonstrated that GNE-7915 and 19 are moderately potent 5-HT2B antagonists [2].
ln Vivo	In rats, GNE-7915 demonstrates excellent in vivo PK profiles with long half-lives, good oral exposure and high passive permeability. GNE-7915 (50 mg/kg i.p. or p.o.) results in concentration-dependent knockdown of pLRRK2 in the brain of BAC transgenic mice expressing human LRRK2 protein with the G2019S Parkinson’s disease mutation.
Animal Protocol	Dissolved in 1% methylcellulose in water; 50 mg/kg; i.p. injection and p.o. BAC transgenic mice expressing human LRRK2 protein with the G2019S Parkinson’s disease mutation
References	[1]. The development of CNS-active LRRK2 inhibitors using property-directed optimisation. Bioorg Med Chem Lett.?2013 Jul 1;23(13):3690-6. [2]. Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem. 2012 Nov 26;55(22):9416-33.

Solubility Data

Solubility (In Vitro)

DMSO: 22 mg/mL (49.6 mM) Water:<1 mg/mL Ethanol:<1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.64 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (5.64 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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 3: ≥ 2.5 mg/mL (5.64 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: ≥ 2.5 mg/mL (5.64 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2553 mL	11.2765 mL	22.5530 mL
	5 mM	0.4511 mL	2.2553 mL	4.5106 mL
	10 mM	0.2255 mL	1.1276 mL	2.2553 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.