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

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.
Matthew Spock 1,  Trever R Carter 1,  Katrina A Bollinger 1,  Changho Han 1,  Logan A Baker 1,  Alice L Rodriguez 1,  Li Peng 1,  Jonathan W Dickerson 1,  Aidong Qi 1,  Jerri M Rook 1,  Jordan C O'Neill 1,  Katherine J Watson 1,  Sichen Chang 1,  Thomas M Bridges 1,  Julie L Engers 1,  Darren W Engers 1,  Colleen M Niswender 1,  P Jeffrey Conn 1,  Craig W Lindsley 1,  Aaron M Bender 1
Affiliations

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.
PMID: 34413964 DOI: 10.1021/acsmedchemlett.1c00363
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.

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