molecules of the month

“compound 24”

LRRK2 kinase inhibitor

preclinical, brain-penetrant

from rational HTL and structure-guided opt.

Journal of Medicinal Chemistry

Merck & Co., Boston, MA

Chemical structure of molecule compound 24 LRRK2
1 min read

LRRK2 is a target of interest for Parkinson’s disease (e.g. DNL-151), but development had been slowed by concerns about potential lung toxicity of LRRK2 inhibitors. A Phase I study of a LRRK2 inhibitor in healthy volunteers had not shown human toxicity, though, and Biogen/Denali plan to proceed with Ph. III and Ph. IIb trials in 2022. The fact that a healthy volunteer study was allowed suggests that preclinical toxicities observed with DNL-151 were likely different from those observed with previous LRRK2 inhibitors. “Compound 24” is a brain-penetrant, type I LRRK2 kinase inhibitor with a distinct structure from previously disclosed LRRK2 inhibitors (e.g. GNE-7915, AZD-3759, MLi-2). The molecule has a rat Kpuu,brain of 0.43 and a projected human dose of 19…

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