Discovery of VU6008677: A Structurally Distinct Tricyclic M Positive Allosteric Modulator with Improved CYP450 Profile

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Aug 14

PMID 39140069

Authors

Rory A Capstick

Sean R Bollinger

Julie L Engers

Madeline F Long

Sichen Chang

Vincent B Luscombe

Alice L Rodriguez

Colleen M Niswender

Thomas M Bridges

Olivier Boutaud

P Jeffrey Conn

Darren W Engers

Craig W Lindsley

Kayla J Temple

Affiliations

Soon will be listed here.

Abstract

This Letter details our efforts to develop novel tricyclic muscarinic acetylcholine receptor subtype 4 (M) positive allosteric modulator (PAM) scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-5-chloro-4,6-dimethylthieno[2,3-]pyridine-2-carboxamide core, which led to the discovery of two novel tricyclic cores: an 8-chloro-9-methylpyrido[3',2':4,5]thieno[3,2-]pyrimidin-4-amine core and 8-chloro-7,9-dimethylpyrido[3',2':4,5]furo[3,2-]pyrimidin-4-amine core. Both tricyclic cores displayed low nanomolar potency against human M and greatly reduced cytochrome P450 inhibition when compared with parent compound .

Citing Articles

Discovery of VU6016235: A Highly Selective, Orally Bioavailable, and Structurally Distinct Tricyclic M Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM).

Engers J, Baker L, Chang S, Luscombe V, Rodriguez A, Niswender C ACS Chem Neurosci. 2024; .

PMID: 39316465 PMC: 11487561. DOI: 10.1021/acschemneuro.4c00465.

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