Publications by authors named "Beatriz García Olmos"

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Discovery of Imidazo[1,2-]pyrazines and Pyrazolo[1,5-]pyrimidines as TARP γ-8 Selective AMPAR Negative Modulators.

ACS Med Chem Lett 2019 Mar 26;10(3):267-272. Epub 2018 Dec 26.

Janssen Research & Development L.L.C., 3210 Merryfield Row, San Diego, California 92121 United States.

This report discloses the discovery and characterization of imidazo[1,2-]pyrazines and pyrazolo[1,5-]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 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 , JNJ-61432059. Following oral administration, 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.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421542PMC
March 2019