Hybrid indazole–bicyclic pyrrole chemotype targets mutant-selective LRRK2
- Structure-guided hybridization of an indazole with an octahydrocyclopenta[c]pyrrole gave a new LRRK2 inhibitor chemotype for Parkinson's disease.
- Early piperidine-containing analogs were potent but barely distinguished wild-type from G2019S LRRK2.
- Swapping the piperidine for the fused bicyclic amine was the change introduced to widen that selectivity window.
💡 Points
A narrow wild-type/G2019S window is the usual reason LRRK2 leads stall, so a scaffold change that buys mutant bias is worth a look. I'd want to see whether that bias holds in cells at physiological ATP and what the bicyclic amine does to brain penetration and clearance.