1H-Pyrrolo[3,2-b]pyridine GluN2B-Selective Negative Allosteric Modulators
| Autor: | Akinola Soyode-Johnson, Michael A. Letavic, Kevin J. Coe, Christa C. Chrovian, Brian Lord, Nicholas I. Carruthers, Wall Jessica L, Bartosz Balana, Xiaohui Jiang, Tatiana Koudriakova, Leslie Nguyen, Jason C. Rech, Jeff Schoellerman |
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| Rok vydání: | 2019 |
| Předmět: |
biology
010405 organic chemistry Stereochemistry Organic Chemistry Allosteric regulation hERG Cytochrome P450 01 natural sciences Biochemistry In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound chemistry In vivo Drug Discovery Pyridine biology.protein Potency Receptor |
| Zdroj: | ACS Medicinal Chemistry Letters. 10:261-266 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.8b00542 |
| Popis: | Herein, we disclose a series of selective GluN2B negative allosteric modulators containing a 1H-pyrrolo[3,2-b]pyridine core. Lead optimization efforts included increasing brain penetration as well as decreasing cytochrome P450 inhibition and hERG channel binding. The series was also optimized to reduce metabolic turnover in human and rat. Compounds 9, 25, 30, and 34 have good in vitro GluN2B potency and good predicted absorption, but moderate to high projected clearance. They were assessed in vivo to determine their target engagement. All four compounds achieved >75% receptor occupancy after an oral dose of 10 mg/kg in rat. Compound 9 receptor occupancy was measured in a dose-response experiment, and its ED50 was found to be 2.0 mg/kg. |
| Databáze: | OpenAIRE |
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