Discovery of G2019S Mutant Selective LRRK2 Inhibitors Based on an Indazole Octahydrocyclopenta[ c ]pyrrole-Based Hybrid Chemotype

Abstract LRRK2 is an important kinase target for Parkinson’s disease with disease-modifying potential. In this article, we report our efforts to identify indazole octahydrocyclopenta[c]pyrrole-based hybrid chemotypes as LRRK2 inhibitors utilizing a structure-guided hybridization approach. The initial set of compounds with a piperidine motif showed favorable potencies, but had a rather narrow selectivity window between wild-type and G2019S mutant LRRK2. In contrast, the replacement of the piperidine motif with an octahydrocyclopenta[c]pyrrole enhanced the selectivity window while maintaining good potencies. In short, the presented hybrid chemotype represented by 34 can serve as an alternative starting point and may enable the discovery of next-generation LRRK2 inhibitors through subsequent optimization campaigns.