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
| العنوان: | 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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| المؤلفون: | Alexandra S Needham, Akinola Soyode-Johnson, Kevin J. Coe, Bartosz Balana, Freddy Schoetens, Xiaohui Jiang, Daniel J. Pippel, Kia Sepassi, Chungfang Xia, Stenne Brice M, Brian Scott, Leslie Nguyen, Tatiana Koudriakova, Christa C. Chrovian, Brian Lord, Michael A. Letavic, Jeffrey Schoellerman |
| المصدر: | Journal of Medicinal Chemistry. 63:9181-9196 |
| بيانات النشر: | American Chemical Society (ACS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0303 health sciences, Allosteric regulation, Target engagement, Pharmacology, medicine.disease, 01 natural sciences, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, 03 medical and health sciences, chemistry.chemical_compound, Mood disorders, chemistry, Drug Discovery, medicine, Molecular Medicine, Major depressive disorder, Structure–activity relationship, Ionotropic glutamate receptor, Receptor, Lead compound, 030304 developmental biology |
| الوصف: | 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. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::19f1743cefc51ebca30728bea44390f7 https://doi.org/10.1021/acs.jmedchem.9b02113 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi...........19f1743cefc51ebca30728bea44390f7 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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