Discovery and Optimization of Potent and CNS Penetrant M5-Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold

The pharmacology of the M-5 muscarinic acetylcholine receptor (mAChR) is the least understood of the five mAChR subtypes due to a historic lack of selective small molecule tools. To address this shortcoming, we have continued the optimization effort around the prototypical M-5 positive allosteric modulator (PAM) ML380 and have discovered and optimized a new series of M-5 PAMs based on a chiral N-(indanyl)piperidine amide core with robust SAR, human and rat M-5 PAM EC50 values <100 nM and rat brain/plasma K-P values of similar to 0.40. Interestingly, unlike M, and M-4 PAMs with unprecedented mAChR subtype selectivity, this series of M-5 PAMs displayed varying degrees of PAM activity at the other two natively G(q)-coupled mAChRs, M, and M-3, yet were inactive at M-2 and M-4.