%0 Journal Article
%T Discovery of Imidazo[1,2-a]pyrazines and Pyrazolo[1,5-c]pyrimidines as TARP ¦Ã-8 Selective AMPAR Negative Modulators
%J -
%D 2019
%R https://doi.org/10.1021/acsmedchemlett.8b00599
%X This report discloses the discovery and characterization of imidazo[1,2-a]pyrazines and pyrazolo[1,5-c]pyrimidines as selective negative modulators of ¦Á-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein ¦Ã-8. Imidazopyrazine 5 was initially identified as a promising ¦Ã-8 selective high-throughput screening hit, and subsequent structure¨Cactivity 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/¦Ã-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models
%U https://pubs.acs.org/doi/10.1021/acsmedchemlett.8b00599