The paper describes discovery and optimization of CNS-penetrant, selective macrocyclic LRRK2 inhibitors, overcoming genotoxicity and PXR/kinome liabilities to produce lead compound 12 with good brain exposure and a low projected human dose.

LRRK2 is a genetically validated PD target, so a potent, brain-penetrant, nongenotoxic inhibitor with favorable selectivity and dosing potential is a strong preclinical candidate for translation toward Parkinson's disease therapies.

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.