Discovery and\nOptimization of N‑Heteroaryl\nIndazole LRRK2 Inhibitors

Inhibition of leucine-rich repeat kinase 2 is a genetically\nsupported\nmechanism for the treatment of Parkinson’s disease. We previously\ndisclosed the discovery of an indazole series lead that demonstrated\nboth safety and translational risks. The safety risks were hypothesized\nto be of unknown origin, so structural diversity in subsequent chemical\nmatter was prioritized. The translational risks were identified due\nto a low brain Kp<sub>u,u</sub> in nonhuman primate studies, which\nraised concern over the use of an established peripheral biomarker\nas a surrogate for central target engagement. Given these challenges,\nthe team sought to leverage structure- and property-based drug design\nand expanded efflux transporter profiling to identify structurally\ndistinct leads with enhanced CNS drug-likeness. Herein, we describe\nthe discovery of a “reinvented” indazole series with\nimproved physicochemical properties and efflux transporter profiles\nwhile maintaining excellent potency and off-target kinase selectivity,\nwhich resulted in advanced lead, compound <b>23</b>.