Application of Deuterium in an M₁ 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 desired profile of minimal M₁ agonism. Overall, the profile of VU6045422 supported advancement, as did greater <i>in vitro</i> metabolic stability in both microsomes and hepatocytes than did VU0467319. In both rat and dog <i>in vivo</i>, low doses proved to mirror the <i>in vitro</i> 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.