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Design, Synthesis, and Preclinical Evaluation of 3‑Methyl-6-(5-thiophenyl)-1,3-dihydro-imidazo[4,5‑b]pyridin-2-ones as Selective GluN2B Negative Allosteric Modulators for the Treatment of Mood Disorders

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journal contribution
posted on 29.08.2020, 00:14 by Christa C. Chrovian, Akinola Soyode-Johnson, Brice Stenne, Daniel J. Pippel, Jeffrey Schoellerman, Brian Lord, Alexandra S. Needham, Chungfang Xia, Kevin J. Coe, Kia Sepassi, Freddy Schoetens, Brian Scott, Leslie Nguyen, Xiaohui Jiang, Tatiana Koudriakova, Bartosz Balana, Michael A. Letavic
Selective inhibitors of the GluN2B subunit of N-methyl-d-aspartate receptors in the ionotropic glutamate receptor superfamily have been targeted for the treatment of mood disorders. We sought to identify structurally novel, brain penetrant, GluN2B-selective inhibitors suitable for evaluation in a clinical setting in patients with major depressive disorder. We identified a new class of negative allosteric modulators of GluN2B that contain a 1,3-dihydro-imidazo­[4,5-b]­pyridin-2-one core. This series of compounds had poor solubility properties and poor permeability, which was addressed utilizing two approaches. First, a series of structural modifications was conducted which included replacing hydrogen bond donor groups. Second, enabling formulation development was undertaken in which a stable nanosuspension was identified for lead compound 12. Compound 12 was found to have robust target engagement in rat with an ED70 of 1.4 mg/kg. The nanosuspension enabled sufficient margins in preclinical toleration studies to nominate 12 for progression into advanced good laboratory practice studies.