3-(Pyridin-2-Yl-Ethynyl)Benzamide Metabotropic Glutamate Receptor 5 Negative Allosteric Modulators: Hit To Lead Studies

A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC50: 926 nM), potent mGluR5 NAMs showing excellent potencies (IC(50)s < 50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (K-i: 21 nM) and antagonism (IC50: 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk). (C) 2010 Elsevier Ltd. All rights reserved.