1285515-21-0

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

GSK2578215A is a potent inhibitor of leucine-rich repe at kinase-2 (LRRK2) also known as dardarin or PARK8a kinase with mutations linked to Parkinson′s disease. Because the most common mutationG2019Senhances LRRK2 kinase activityit 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 fragmentationautophagy and mitophagy.

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.

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[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