Discovery of VU6028418: A Highly Selective and Orally Bioavailable M4 Muscarinic Acetylcholine Receptor Antagonist.
Matthew SpockTrever R CarterKatrina A BollingerChangho HanLogan A BakerAlice L RodriguezLi PengJonathan W DickersonAidong QiJerri M RookJordan C O'NeillKatherine J WatsonSichen ChangThomas M BridgesJulie L EngersDarren W EngersColleen M NiswenderP Jeffrey ConnDennis C LiottaAaron M BenderPublished in: ACS medicinal chemistry letters (2021)
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.