biostudies-literatureEngers JLACADIA PharmaceuticalsNIMH NIH HHSWilliam K. Warren FoundationNational Institute of Mental HealthVanderbilt University1582-1591https://www.ebi.ac.uk/biostudies/studies/S-EPMC12006963biostudies-literatureUnknown16(8)Recently, we disclosed VU0467319, an M₁ 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 M₁ PAM (human EC₅₀ = 192 nM, 80% ACh Max) than its proteocongener VU0467319 (human EC₅₀ = 492 nM, 71% ACh Max), and retained the desiACS chemical neuroscienceApplication of Deuterium in an M<sub>1</sub> Positive Allosteric Modulator Back-Up Program: The Discovery of VU6045422.PMC12006963MH108498R01 MH082867UNIV61505MH073676R01 MH073676MH082867R01 MH108498O'Carroll CConn PJEngers DWLi JPeng WNiswender CMBurstein ESBoutaud ORodriguez ALPresley CCDickerson JWEngers JLLindsley CWGregro ARDey PMXiang ZHan CRook JMLong MFCho HPfalseApplication of Deuterium in an M<sub>1</sub> Positive Allosteric Modulator Back-Up Program: The Discovery of VU6045422.Recently, we disclosed VU0467319, an M₁ 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 M₁ PAM (human EC₅₀ = 192 nM, 80% ACh Max) than its proteocongener VU0467319 (human EC₅₀ = 492 nM, 71% ACh Max), and retained the desi2025-01-01T00:00:00Z2025 Apr2025-06-28T03:05:39.612Z2025-06-28T03:05:39.612ZS-EPMC120069634013202310.1021/acschemneuro.5c00119