Discovery of Imidazo[1,2-a]pyrazines and Pyrazolo[1,5-c]pyrimidines as TARP γ-8 Selective AMPAR Negative Modulators
| Autor: | Tatiana Koudriakova, Devin M. Swanson, Dongpei Wu, Nicholas I. Carruthers, Kevin J. Coe, Timothy W. Lovenberg, Michael K. Ameriks, Mark Seierstad, Beatriz García Olmos, Jorge Vives Martinez, Nyantsz Wu, Brian Lord, Michael P. Maher, Brad M. Savall |
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| Rok vydání: | 2018 |
| Předmět: |
010405 organic chemistry
medicine.medical_treatment Organic Chemistry Glutamate receptor AMPA receptor Glutathione Pharmacology 01 natural sciences Biochemistry Pyrazolopyrimidine Transmembrane protein 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry.chemical_compound Anticonvulsant chemistry Drug Discovery medicine Efflux Receptor |
| Zdroj: | ACS Medicinal Chemistry Letters. 10:267-272 |
| ISSN: | 1948-5875 6143-2059 |
| Popis: | [Image: see text] This report discloses the discovery and characterization of imidazo[1,2-a]pyrazines and pyrazolo[1,5-c]pyrimidines as selective negative modulators of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein γ-8. Imidazopyrazine 5 was initially identified as a promising γ-8 selective high-throughput screening hit, and subsequent structure–activity relationship optimization yielded subnanomolar, brain penetrant leads. Replacement of the imidazopyrazine core with an isosteric pyrazolopyrimidine scaffold improved microsomal stability and efflux liabilities to provide 26, JNJ-61432059. Following oral administration, 26 exhibited time- and dose-dependent AMPAR/γ-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models. |
| Databáze: | OpenAIRE |
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