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

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.

SUBMITTER: Spock M

PROVIDER: S-EPMC8366002 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

Spock Matthew M Carter Trever R TR Bollinger Katrina A KA Han Changho C Baker Logan A LA Rodriguez Alice L AL Peng Li L Dickerson Jonathan W JW Qi Aidong A Rook Jerri M JM O'Neill Jordan C JC Watson Katherine J KJ Chang Sichen S Bridges Thomas M TM Engers Julie L JL Engers Darren W DW Niswender Colleen M CM Conn P Jeffrey PJ Lindsley Craig W CW Bender Aaron M AM

ACS medicinal chemistry letters 20210802 8

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. ...[more]

PMID: 34413964

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