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

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

  • ACS Med Chem Lett. 2018 Dec 26;10(3):267-272. doi: 10.1021/acsmedchemlett.8b00599.
Brad M Savall 1,  Dongpei Wu 2,  Devin M Swanson 2,  Mark Seierstad 2,  Nyantsz Wu 2,  Jorge Vives Martinez 3,  Beatriz García Olmos 3,  Brian Lord 2,  Kevin Coe 2,  Tatiana Koudriakova 2,  Timothy W Lovenberg 2,  Nicholas I Carruthers 2,  Michael P Maher 2,  Michael K Ameriks 2
Affiliations

Affiliations

  • 1 Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, United States.
  • 2 Janssen Research & Development L.L.C., 3210 Merryfield Row, San Diego, California 92121 United States.
  • 3 Eurofins-Villapharma Research S.L., Parque Tecnológico de Fuente Alamo, Carretera El Estrecho-Lobosilo, Km. 2,5, E-30320 Fuente Alamo (Murcia), Spain.
PMID: 30891124 DOI: 10.1021/acsmedchemlett.8b00599
Abstract

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.

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