AMPA receptors (AMPARs) are glutamate-gated ion channels that mediate the majority of fast synaptic transmission within the central nervous system (CNS). Although AMPARs are widely expressed throughout the CNS, their activity can be modulated by auxiliary proteins such as transmembrane regulatory proteins (TARPs), which are often localized in distinct brain regions. Herein, we describe the medicinal chemistry efforts that led to the identification of JNJ-55511118, a selective negative modulator of AMPARs dependent upon TARP-γ8, which is the primary TARP expressed in the hippocampus. Following oral dosing in rodents, JNJ-55511118 exhibited dose-dependent receptor occupancy as determined by <i>ex vivo </i>autoradiography and also provided strong seizure protection with minimal impairment of learning, memory, and motor function.<br/>

Identification and optimization of 5-aryl benzimidazolones as AMPA receptor negative modulators selective for TARP-γ8

253rd National Meeting (2017)

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