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LRRK2-kinase inhibitor

Product NameLRRK2-kinase inhibitor
CAS1285515-21-0
MFC24H18FN3O2
MW399.42
EINECS
MOL File1285515-21-0.mol

Chemical Properties

Boiling point	556.1±50.0 °C(Predicted)
Density	1.292±0.06 g/cm3(Predicted)
storage temp.	2-8°C
solubility	DMSO: soluble15mg/mL, clear
form	powder
pka	12.31±0.70(Predicted)
color	white to beige
InChI	1S/C24H18FN3O2/c25-23-14-19(10-12-27-23)18-8-9-22(30-16-17-5-2-1-3-6-17)21(13-18)24(29)28-20-7-4-11-26-15-20/h1-15H,16H2,(H,28,29)
InChIKey	WCIGMFCFPXZRMQ-UHFFFAOYSA-N
SMILES	Fc1nccc(c1)c2cc(c(cc2)OCc4ccccc4)C(=O)Nc3cnccc3

Safety Information

WGK Germany	3
Storage Class	11 - Combustible Solids

Usage And Synthesis

Uses

GSK2578215A is a potent, selective LRRK2 inhibitor and a promising therapeutic for treating Parkinson''s disease.

Biological Activity

GSK2578215A is a potent inhibitor of leucine-rich repe at kinase-2 (LRRK2) also known as dardarin or PARK8, a kinase with mutations linked to Parkinson′s disease. Because the most common mutation, G2019S, enhances LRRK2 kinase activity, it is hoped th at LRRK2 inhibitors may be useful in treating the disease. GSK2578215A inhibited both wild-type and G2019S mutant LRRK2 kinase activity with IC50s of 10.9 and 8.9 nM respectively. It has good blood-brain barrier (BBB) permeability with a high ratio of brain to plasma distribution in mice.', 'GSK2578215A stimulates mitochondrial fragmentation, autophagy and mitophagy.

Synthesis

2-(benzyloxy)-5-bromo-N-(pyridin-3-yl)benzamide

1285513-32-7

401815-98-3

1285515-21-0

Compound (CAS: 1285513-32-7) (771 mg, 2.012 mmol) and 2-fluoro-4-pyridineboronic acid (425 mg, 3.02 mmol) were used as raw materials in the presence of bis(triphenylphosphine)palladium(II) chloride (70.6 mg, 0.101 mmol) and sodium carbonate (1066 mg, 10.06 mmol), and in a solvent mixture of DME (20 mL) and water (2 mL) was stirred at reflux for 2 hours. After completion of the reaction, the mixture was diluted with ethyl acetate (50 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL x 2). The organic layers were combined, concentrated, and the crude product was purified by silica gel column chromatography using 0-10% methanol/dichloromethane (containing 1% ammonia) as eluent to afford 2-(benzyloxy)-5-(2-fluoropyridin-4-yl)-N-(pyridin-3-yl)benzamide (500 mg, 1.252 mmol, 62.2% yield) as an off-white solid.

in vivo

GSK2578215A (5 mg/kg, i.p.) with Olaparib (HY-10162) (50mg/kg, i.p., T.I.W for 3 weeks) effectively inhibits the tumor growth in mice bearing OVCAR8 xenografts^[3].
GSK2578215A (IV, 1 mg/kg, or PO, 10 mg/kg) achieves an exposure in the brain with a brain to plasma ratio of 1.4 (IV) and 2.4 (PO), and shows low oral bioavailability (IV, 12.2%), a half-life of 1.14 h (IV) and plasma exposure (PO, 635.3 h ng/mL, AUC_last)^[1].

Animal Model:	mice bearing OVCAR8 xenografts^[3]
Dosage:	5 mg/kg, with Olaparib (50mg/kg)
Administration:	i.p., for 3 weeks
Result:	Inhibited the tumor growth and increased DNA damage in tumors more potently than Olaparib or GSK2578215A alone.

storage

Store at RT

References

[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 17, p. 4034 - 4038
[2] Patent: WO2011/38572, 2011, A1. Location in patent: Page/Page column 158; 159

LRRK2-kinase inhibitor

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