Discovery of VU0467319: an M₁ Positive Allosteric Modulator Candidate That Advanced into Clinical Trials.

ABSTRACT: Herein we detail the first disclosure of VU0467319 (VU319), an M₁ Positive Allosteric Modulator (PAM) clinical candidate that successfully completed a Phase I Single Ascending Dose (SAD) clinical trial. VU319 (16) is a moderately potent M₁ PAM (M₁ PAM EC₅₀ = 492 nM ± 2.9 nM, 71.3 ± 9.9% ACh Max), with minimal M₁ agonism (EC₅₀ > 30 μM), that displayed high CNS penetration (K_ps > 0.67 and K_p,uus > 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)

SUBMITTER: Poslunsey MS 

PROVIDER: S-EPMC11697341 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature