{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Engers JL"],"funding":["ACADIA Pharmaceuticals","NIMH NIH HHS","William K. Warren Foundation","National Institute of Mental Health","Vanderbilt University"],"pagination":["1582-1591"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12006963"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["16(8)"],"pubmed_abstract":["Recently, we disclosed VU0467319, an M<sub>1</sub> positive allosteric modulator (PAM) clinical candidate that had successfully completed a phase I single ascending dose clinical trial. Pharmacokinetic assessment revealed that, in humans upon increasing dose, a circulating, inactive metabolite constituted a major portion of the total drug-related area under the curve (AUC). One approach the team employed to reduce inactive metabolite formation in the back-up program was the kinetic isotope effect, replacing the metabolically labile C-H bonds with shorter, more stable C-D bonds. The C-D dipole afforded VU6045422, a more potent M<sub>1</sub> PAM (human EC<sub>50</sub> = 192 nM, 80% ACh Max) than its proteocongener VU0467319 (human EC<sub>50</sub> = 492 nM, 71% ACh Max), and retained the desi"],"journal":["ACS chemical neuroscience"],"pubmed_title":["Application of Deuterium in an M&lt;sub&gt;1&lt;/sub&gt; Positive Allosteric Modulator Back-Up Program: The Discovery of VU6045422."],"pmcid":["PMC12006963"],"funding_grant_id":["MH108498","R01 MH082867","UNIV61505","MH073676","R01 MH073676","MH082867","R01 MH108498"],"pubmed_authors":["O'Carroll C","Conn PJ","Engers DW","Li J","Peng W","Niswender CM","Burstein ES","Boutaud O","Rodriguez AL","Presley CC","Dickerson JW","Engers JL","Lindsley CW","Gregro AR","Dey PM","Xiang Z","Han C","Rook JM","Long MF","Cho HP"],"additional_accession":[]},"is_claimable":false,"name":"Application of Deuterium in an M&lt;sub&gt;1&lt;/sub&gt; Positive Allosteric Modulator Back-Up Program: The Discovery of VU6045422.","description":"Recently, we disclosed VU0467319, an M<sub>1</sub> positive allosteric modulator (PAM) clinical candidate that had successfully completed a phase I single ascending dose clinical trial. Pharmacokinetic assessment revealed that, in humans upon increasing dose, a circulating, inactive metabolite constituted a major portion of the total drug-related area under the curve (AUC). One approach the team employed to reduce inactive metabolite formation in the back-up program was the kinetic isotope effect, replacing the metabolically labile C-H bonds with shorter, more stable C-D bonds. The C-D dipole afforded VU6045422, a more potent M<sub>1</sub> PAM (human EC<sub>50</sub> = 192 nM, 80% ACh Max) than its proteocongener VU0467319 (human EC<sub>50</sub> = 492 nM, 71% ACh Max), and retained the desi","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Apr","modification":"2025-06-28T03:05:39.612Z","creation":"2025-06-28T03:05:39.612Z"},"accession":"S-EPMC12006963","cross_references":{"pubmed":["40132023"],"doi":["10.1021/acschemneuro.5c00119"]}}