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

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

doi:10.1021/acsmedchemlett.1c00363.s001

ml1c00363_si_001.pdf (948.78 kB)

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

journal contribution

posted on 2021-08-02, 21:13 authored by 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

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.