Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu₃ NAMs

Herein, we detail the optimization of the mGlu₃ NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu₃ NAM scaffold that engenders potent and selective mGlu₃ inhibition (mGlu₃ IC₅₀ = 245 nM, mGlu₂ IC₅₀ > 30 μM) with excellent central nervous system penetration (rat brain/plasma K_p = 1.2, K_p,uu = 0.40). Moreover, this new chemotype, exemplified by VU6010572, requires only four synthetic steps and displays improved physiochemical properties and in vivo efficacy in a mouse tail suspension test (MED = 3 mg/kg i.p.).