GNE-7915

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GNE-7915

本产品不向个人销售，仅用作科学研究，不用于任何人体实验及非科研性质的动物实验。

CAS NO:	1351761-44-8
规格:	≥98%

包装与价格：

包装	价格(元)
50mg	询价
100mg	询价
250mg	询价
500mg	询价
1g	询价

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.

理化性质和储存条件

Molecular Weight (MW)	443.40
Formula	C19H21F4N5O3
CAS No.	1351761-44-8
Storage	-20℃ for 3 years in powder form
Storage	-80℃ for 2 years in solvent
Solubility (In vitro)	DMSO: 22 mg/mL (49.6 mM)
	Water: <1 mg/mL
	Ethanol: <1 mg/mL
SMILES	O=C(C1=CC(OC)=C(NC2=NC=C(C(F)(F)F)C(NCC)=N2)C=C1F)N3CCOCC3
Synonyms	GNE 7915; GNE-7915; GNE7915; Chemical Name: (4-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone 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) SMILES Code: O=C(C1=CC(OC)=C(NC2=NC=C(C(F)(F)F)C(NCC)=N2)C=C1F)N3CCOCC3

实验参考方法

In Vitro	In vitro activity: GNE-7915 is also a moderately potent 5-HT2B antagonist according to in vitro functional assays. GNE-7915 demonstrates excellent in vitro DMPK with minimal turnover in human hepatocytes. Kinase Assay: Maintaining the methoxy/fluoro arrangement at C-2′/C-5′ and varying aminoalkyl R1 substitution resultes in single-digit nanomolar LRRK2 cellular activities for GNE-7915 and compound 19. Expanded Invitrogen kinase profiling (187 kinases) at 0.1 μM for both GNE-7915 (100-fold over LRRK2 Ki) and 19 (250-fold over LRRK2 Ki) resultes in only TTK showing greater than 50% inhibition. Selectivity profiling using the DiscoverX KinomeScan55 competitive binding assay panel, which includes 392 unique kinases, is also performed for GNE-7915 at 0.1 μM. Binding of>50% probe displacement is detected for 10 kinases and of>65% for only LRRK2, TTK, and ALK, further supporting the excellent LRRK2 selectivity for GNE-7915. Cerep receptor profiling, including expanded brain panels, suggestes that GNE-7915 and 19 only inhibite 5-HT2B with>70% inhibition at 10 μM. GNE-7915 and 19 are confirmed to be moderately potent 5-HT2B antagonists in vitro functional assays. Cell Assay: GNE-7915 is a novel, highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) inhibitor, with IC50 and Ki of 9 nM and 1 nM, respectively.
In 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 model	BAC transgenic mice expressing human LRRK2 protein with the G2019S Parkinson’s disease mutation
Formulation & Dosage	Dissolved in 1% methylcellulose in water; 50 mg/kg; i.p. injection and p.o.
References	J Med Chem. 2012 Nov 26;55(22):9416-33