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 Kp = 1.2, Kp,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.).