Bioorg Med Chem Lett 2021 Jun 9;47:128193. Epub 2021 Jun 9.
Warren Center for Neuroscience Drug Discovery, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address:
This Letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) of the muscarinic acetylcholine receptor M (mAChR M). Through the continued optimization of M 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 PAMs with structurally novel chemotypes is disclosed. Two compounds from these subseries, 8b (VU6005610) and 20a (VU6005852), show robust selectivity for the M mAChR, and no M agonism. Read More