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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:47

Article

Spearing, Paul K.^1,2  Cho, Hyekyung P.^1,2  Luscombe, Vincent B.^1,2  Blobaum, Anna L.^1,2  Boutaud, Olivier^1,2  Engers, Darren W.^1,2  Rodriguez, Alice L.^1,2  Niswender, Colleen M.^1,2,3  Conn, P. Jeffrey^1,2,3  Lindsley, Craig W.^1,2,4,5  Bender, Aaron M.^1,2 

[1] Warren Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Dept Pharmacol, Sch Med, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Pharmacol, Vanderbilt Kennedy Ctr, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[5] Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA

关键词: Muscarinic acetylcholine receptor;    Positive allosteric modulator;    Structure-activity relationship;   

DOI  :  10.1016/j.bmcl.2021.128193

来源: Elsevier

【 摘 要 】

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.

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