Discovery of Potent, Selective, CNS-Penetrant Macrocyclic LRRK2 Inhibitors for the Treatment of Parkinson’s Disease

Genetic mutations in the leucine-rich repeat kinase 2
(LRRK2) protein
have been linked to Parkinson’s disease (PD), a disabling and
progressive neurodegenerative disorder for which treatments are limited.
Herein, we describe the invention of a macrocyclic LRRK2 inhibitor
lead chemical series. Rigorous application of knowledge-, structure-,
and property-based drug design culminated in the discovery of compound 7, which was profiled extensively before it was determined
to be clastogenic, which halted its progression. Parallel optimization
of kinome selectivity and PXR activation through structure- and property-based
drug design resulted in the discovery of the lead macrocycle compound 12. This macrocycle boasts a remarkably low projected human
QD dose, is nongenotoxic, and achieved encouraging brain penetration
in early preclinical models.