Discovery of VU6052254: A Novel, Potent M ₁ Positive Allosteric Modulator

We recently disclosed VU0467319, a muscarinic acetylcholine receptor subtype 1 (M₁) Positive Allosteric Modulator (PAM) clinical candidate that had successfully completed a Phase I Single Ascending Dose (SAD) clinical trial, but the identification of an inactive metabolite constituting a major portion of the total plasma AUC detracted from the molecules' pharmacokinetic profile and contributed to clinical development discontinuation. Attempts to block metabolism with the incorporation of deuterium atoms proved successful <i>in vitro</i> and <i>in vivo</i> at low exposures; however, in high-dose nonclinical toxicology studies, the degree of oxidative metabolism and metabolite accumulation was comparable to that of the proteo-congener. Here, we describe a second-generation back-up effort based on the VU0467319 scaffold to discover VU6052254. Strategic placement of a tertiary hydroxyl moiety afforded VU6052254, a potent M₁ PAM (EC₅₀ = 59 nM, 79% ACh max), with high CNS exposure (rat K_p = 1.07; K_p,uu = 1.27; P-gp ER = 1.97, P_app = 23 × 10^-6 cm/s), reduced metabolism across species, excellent pharmacodynamic responses (MED in rat NOR = 1 mg/kg PO; MED in rat CFC = 0.3 mg/kg PO), excellent multispecies PK (Cl_p<i>s</i> < 10 mL/min/kg, %<i>F</i> > 65), and favorable human PK and dose projections. Based on these beneficial attributes, VU6052254 was nominated for further nonclinical development. However, possible CYP₄₅₀ induction liability as well as uncertain projected margins for human efficacy at those systemic concentrations where dose/exposure-related clinical and anatomic pathology kidney findings were observed in a 14-day exploratory toxicity study in male rats, precluded further development.