Discovery of a novel class of heteroaryl-pyrrolidinones as positive allosteric modulators of the muscarinic acetylcholine receptor M1

This Letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) of the muscarinic acetylcholine receptor M-1 (mAChR M-1). Through the continued optimization of M-1 PAM tool compound VU0453595, with a focus on replacement of the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one with a wide variety of alternative 4,5-dihydropyrrolo-fused heteroaromatics, the generation of M-1 PAMs with structurally novel chemotypes is disclosed. Two compounds from these subseries, 8b (VU6005610) and 20a (VU6005852), show robust selectivity for the M-1 mAChR, and no M-1 agonism. Both compounds have favorable preliminary PK profiles in vitro; 8b additionally demonstrates high brain exposure in a rodent IV cassette model.

Automated summary

This letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) for the muscarinic acetylcholine receptor M-1 (mAChR M-1). Through continued optimization, two compounds, 8b (VU6005610) and 20a (VU6005852), were found to have robust selectivity for the M-1 mAChR with no agonism. Additionally, compound 8b showed high brain exposure in a rodent IV cassette model.