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3-Benzyl-1,3-oxazolidin-2-ones as mGluR2 positive allosteric modulators: Hit-to lead and lead optimization |
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| Authors: | Allen J Duplantier Ivan Efremov John Candler Angela C Doran Alan H Ganong Jessica A Haas Ashley N Hanks Kenneth G Kraus John T Lazzaro Jiemin Lu Noha Maklad Sheryl A McCarthy Theresa J O’Sullivan Bruce N Rogers Judith A Siuciak Douglas K Spracklin Lei Zhang |
| Institution: | 1. CNS Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA;2. Lead Generation Group, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA;3. Department of Neuroscience, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA;4. Department of Pharmacokinetics and Drug Metabolism, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA |
| Abstract: | The discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs. |
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