Abstact

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.