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

Paul K Spearing; Hyekyung P Cho; Vincent B Luscombe; Anna L Blobaum; Olivier Boutaud; Darren W Engers; Alice L Rodriguez; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Aaron M Bender

doi:10.1016/j.bmcl.2021.128193

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

Bioorg Med Chem Lett. 2021 Sep 1:47:128193. doi: 10.1016/j.bmcl.2021.128193. Epub 2021 Jun 9.

Affiliations

¹ Warren Center for Neuroscience Drug Discovery, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.
² Warren Center for Neuroscience Drug Discovery, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.
³ Warren Center for Neuroscience Drug Discovery, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States; Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, United States.
⁴ 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: [email protected].

Abstract

This Letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) of the muscarinic acetylcholine receptor M₁ (mAChR M₁). Through the continued optimization of M₁ 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 M₁ PAMs with structurally novel chemotypes is disclosed. Two compounds from these subseries, 8b (VU6005610) and 20a (VU6005852), show robust selectivity for the M₁ mAChR, and no M₁ agonism. Both compounds have favorable preliminary PK profiles in vitro;8b additionally demonstrates high brain exposure in a rodent IV cassette model.

Keywords: Muscarinic acetylcholine receptor; Positive allosteric modulator; Structure-activity relationship.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation / drug effects
Animals
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Molecular Structure
Pyrrolidinones / chemical synthesis
Pyrrolidinones / chemistry
Pyrrolidinones / pharmacology*
Rats
Receptor, Muscarinic M1 / agonists*
Structure-Activity Relationship

Substances

Pyrrolidinones
Receptor, Muscarinic M1