LRRK2-kinase inhibitor

LRRK2-kinase inhibitor Property

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

Safety

WGK Germany 

3

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P271Use only outdoors or in a well-ventilated area.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P304+P340IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P312Call a POISON CENTER or doctor/physician if you feel unwell.

P321Specific treatment (see … on this label).

P332+P313IF SKIN irritation occurs: Get medical advice/attention.

P337+P313IF eye irritation persists: Get medical advice/attention.

P362Take off contaminated clothing and wash before reuse.

P403+P233Store in a well-ventilated place. Keep container tightly closed.

P405Store locked up.

P501Dispose of contents/container to..…

LRRK2-kinase inhibitor Chemical Properties,Usage,Production

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

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

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