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

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

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

Author(s) -

Matthew Spock,

Trever R. Carter,

Katrina A. Bollinger,

Changho Han,

Logan A. Baker,

Alice L. Rodriguez,

Peng Li,

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

Publication year - 2021

Publication title -

acs medicinal chemistry letters

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.065

H-Index - 66

ISSN - 1948-5875

DOI - 10.1021/acsmedchemlett.1c00363

Subject(s) - antagonist , muscarinic acetylcholine receptor , pharmacology , in vivo , bioavailability , chemistry , acetylcholine , drug discovery , in vitro , muscarinic antagonist , medicine , biology , receptor , biochemistry , genetics

Herein, we report the SAR leading to the discovery of VU6028418, a potent M 4 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.

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