Discovery of VU6028418: A Highly Selective and Orally Bioavailable M4 Muscarinic Acetylcholine Receptor Antagonist

Matthew Spock; Trever R Carter; Katrina A Bollinger; Changho Han; Logan A Baker; Alice L Rodriguez; Li Peng; Jonathan W Dickerson; Aidong Qi; Jerri M Rook; Jordan C O'Neill; Katherine J Watson; Sichen Chang; Thomas M Bridges; Julie L Engers; Darren W Engers; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Aaron M Bender

doi:10.1021/acsmedchemlett.1c00363

Discovery of VU6028418: A Highly Selective and Orally Bioavailable M₄ Muscarinic Acetylcholine Receptor Antagonist

ACS Med Chem Lett. 2021 Aug 2;12(8):1342-1349. doi: 10.1021/acsmedchemlett.1c00363. eCollection 2021 Aug 12.

Authors

Matthew Spock¹, Trever R Carter¹, Katrina A Bollinger¹, Changho Han¹, Logan A Baker¹, Alice L Rodriguez¹, Li Peng¹, Jonathan W Dickerson¹, Aidong Qi¹, Jerri M Rook¹, Jordan C O'Neill¹, Katherine J Watson¹, Sichen Chang¹, Thomas M Bridges¹, Julie L Engers¹, Darren W Engers¹, Colleen M Niswender¹, P Jeffrey Conn¹, Craig W Lindsley¹, Aaron M Bender¹

Affiliation

¹ Warren Center for Neuroscience Drug Discovery, Department of Pharmacology, Department of Chemistry, Department of Biochemistry, and Vanderbilt Kennedy Center, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232, United States.

Abstract

Herein, we report the SAR leading to the discovery of VU6028418, a potent M₄ mAChR antagonist with high subtype-selectivity and attractive DMPK properties in vitro and in vivo across multiple species. VU6028418 was subsequently evaluated as a preclinical candidate for the treatment of dystonia and other movement disorders. During the characterization of VU6028418, a novel use of deuterium incorporation as a means to modulate CYP inhibition was also discovered.