Bicyclic amine swap widens the G2019S window in indazole LRRK2 inhibitors
- Structure-guided hybridization produced an indazole-based LRRK2 series; the initial piperidine compounds were potent but barely distinguished wild-type from G2019S mutant kinase.
- Replacing the piperidine with an octahydrocyclopenta[c]pyrrole widened the selectivity window while keeping good potency; compound 34 represents the new chemotype.
- The authors pitch it as an alternative starting point for next-generation, Parkinson's-directed LRRK2 inhibitors.
💡 Points
Locking a floppy piperidine into a fused bicycle is the textbook way to sharpen selectivity, and it seems to have paid off here. Before getting attached I'd check what the extra carbon framework costs in lipophilicity and brain exposure, because a CNS target punishes both. Mutant-over-wild-type selectivity also needs to hold up in cells, not just in biochemical assays.