VU0467319

VU0467319 (also known as VU319) is a small molecule positive allosteric modulator (PAM) of the muscarinic acetylcholine receptor M1, developed by the Warren Center for Neuroscience Drug Discovery at Vanderbilt University Medical Center. It was investigated for the treatment of Alzheimer's disease and other cognitive disorders, aiming to improve cognitive function by selectively enhancing M1 receptor signaling while avoiding the side effects associated with non-selective muscarinic agonists. Although VU0467319 successfully completed Phase I single and multiple ascending dose clinical trials (NCT03220295) and demonstrated target engagement, its development was discontinued due to the identification of a major inactive circulating metabolite in humans that accounted for a significant portion of drug exposure. Vanderbilt has since partnered with Acadia Pharmaceuticals to pursue next-generation M1 PAM candidates.