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

被引：15

作者：

Sayall, Brad M. ^{[2
]}

Wu, Dongpei ^{[1
]}

Swanson, Devin M. ^{[1
]}

Seierstad, Mark ^{[1
]}

Wu, Nyantsz ^{[1
]}

Vives Martinez, Jorge ^{[3
]}

Garcia Olmos, Beatriz ^{[3
]}

Lord, Brian ^{[1
]}

Coe, Kevin ^{[1
]}

Koudriakova, Tatiana ^{[1
]}

Lovenberg, Timothy W. ^{[1
]}

Carruthers, Nicholas I. ^{[1
]}

Maher, Michael P. ^{[1
]}

Ameriks, Michael K. ^{[1
]}

机构：

[1] Janssen Res & Dev LLC, 3210 Merryfield Row, San Diego, CA 92121 USA

[2] Sanford Burnham Prebys Med Discovery Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA

[3] Eurofins Villapharma Res SL, Parque Tecnol Fuente Alamo, E-30320 Fuente Alamo, Murcia, Spain

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 03期

关键词：

AMPA; a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; TARP gamma-8; transmembrane AMPA receptor regulatory protein; auxiliary subunit; glutamate; hippocampus; epilepsy; glutathione; autoradiography; IONOTROPIC GLUTAMATE RECEPTORS;

D O I：

10.1021/acsmedchemlett.8b00599

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This report discloses the discovery and characterization of imidazo[1,2-a]pyrazines and pyrazolo-[1,5-c]pyrimidines as selective negative modulators of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein gamma-8. Imidazopyrazine 5 was initially identified as a promising gamma-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/gamma-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models.

引用

页码：267 / 272

页数：11

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