3-(Pyridin-2-yl-ethynyl)benzamide metabotropic glutamate receptor 5 negative allosteric modulators: Hit to lead studies
2011
Gilbert, Adam M. | Bursavich, Matthew G. | Lombardi, Sabrina | Adedoyin, Adedayo | Dwyer, Jason M. | Hughes, Zoe | Kern, Jeffrey C. | Khawaja, Xavier | Rosenzweig-Lipson, Sharon | Moore, William J. | Neal, Sarah J. | Olsen, Michael | Rizzo, Stacey J Sukoff | Springer, Dane
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: 926nM), potent mGluR5 NAMs showing excellent potencies (IC₅₀s<50nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (Kᵢ: 21nM) and antagonism (IC₅₀: 8nM), an excellent rat PK profile (CL: 12mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8mpk).
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