Discovery of VU0467319: an M 1 Positive Allosteric Modulator Candidate That Advanced into Clinical Trials.

Herein we detail the first disclosure of VU0467319 (VU319), an M ₁ Positive Allosteric Modulator (PAM) clinical candidate that successfully completed a Phase I Single Ascending Dose (SAD) clinical trial. VU319 ( 16 ) is a moderately potent M ₁ PAM (M ₁ PAM EC ₅₀ = 492 nM ± 2.9 nM, 71.3 ± 9.9% ACh Max), with minimal M ₁ agonism (EC ₅₀ > 30 μM), that displayed high CNS penetration ( K _p s > 0.67 and K _p,uu s > 0.9) and multispecies pharmacokinetics permissive of further development. Based on robust efficacy in multiple preclinical models of cognition, an ancillary pharmacology profile devoid of appreciable off-target activities, and a lack of cholinergic adverse effects (AEs) in rats, dogs and nonhuman primates, VU319 advanced into IND-enabling studies. After completing 4-week rat and dog GLP toxicology without AEs, including absence of cholinergic effects, the first in human Phase I SAD clinical trial of VU319 (NCT03220295) was performed at Vanderbilt, where a similar lack of adverse effects, including absence of cholinergic effects was noted. Moreover, signals of target engagement were seen at the highest dose tested. Thus, VU319 demonstrated the feasibility of achieving selective targeting of central M ₁ muscarinic receptors without eliciting cholinergic AEs that have plagued other drugs targeting CNS cholinergic neurotransmission.