Savall Brad M, Wu Dongpei, Swanson Devin M, Seierstad Mark, Wu Nyantsz, Vives Martinez Jorge, García Olmos Beatriz, Lord Brian, Coe Kevin, Koudriakova Tatiana, Lovenberg Timothy W, Carruthers Nicholas I, Maher Michael P, Ameriks Michael K
Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, California 92037, United States.
Janssen Research & Development L.L.C., 3210 Merryfield Row, San Diego, California 92121 United States.
ACS Med Chem Lett. 2018 Dec 26;10(3):267-272. doi: 10.1021/acsmedchemlett.8b00599. eCollection 2019 Mar 14.
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.
本报告披露了咪唑并[1,2 - ]吡嗪和吡唑并[1,5 - ]嘧啶作为与跨膜AMPA受体调节蛋白γ - 8相关的α - 氨基 - 3 - 羟基 - 5 - 甲基异恶唑 - 4 - 丙酸受体（AMPARs）的选择性负调节剂的发现及特性。咪唑并吡嗪最初被鉴定为一种有前景的γ - 8选择性高通量筛选命中物，随后的构效关系优化产生了亚纳摩尔级、可穿透血脑屏障的先导化合物。用等排体吡唑并嘧啶支架取代咪唑并吡嗪核心改善了微粒体稳定性和外排特性，从而得到了JNJ - 61432059。口服给药后，JNJ - 61432059在小鼠海马体中表现出时间和剂量依赖性的AMPAR/γ - 8受体占有率，这在角膜点燃和戊四氮（PTZ）抗惊厥模型中产生了强大的癫痫保护作用。
