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Application of Deuterium in an M Positive Allosteric Modulator Back-Up Program: The Discovery of VU6045422

Authors

Engers JL Julie L , Li J Jinming , Han C Changho , Long MF Madeline F , Gregro AR Alison R , Presley CC Christopher C , Dickerson JW Jonathan W , Peng W Weimin , Cho HP Hyekyung P , Rodriguez AL Alice L , Xiang Z Zixiu , Boutaud O Olivier , O'Carroll C Colin , Dey PM P Markus , Burstein ES Ethan S , Niswender CM Colleen M , Rook JM Jerri M , Conn PJ P Jeffrey , Engers DW Darren W , Lindsley CW Craig W .
ACS chemical neuroscience. 2025 03 25; 16(8).
1582-1591

Abstract

Recently, we disclosed VU0467319, an M 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 PAM (human EC = 192 nM, 80% ACh Max) than its proteocongener VU0467319 (human EC = 492 nM, 71% ACh Max), and retained the desired profile of minimal M agonism. Overall, the profile of VU6045422 supported advancement, as did greater metabolic stability in both microsomes and hepatocytes than did VU0467319. In both rat and dog , low doses proved to mirror the profile; however, at higher doses in 14-day exploratory toxicology studies, the amount of the same undesired metabolite derived from VU6045422 was equivalent to that produced from VU0467319. This unexpected IVIVC result, coupled with less than dose-proportional increases in exposure and no improvement in solubility, led to discontinuation of VU0467319/VU6045422 development.