Lead Optimization of 5-Aryl Benzimidazolone- and Oxindole-Based AMPA Receptor Modulators Selective for TARP γ-8

Area of Science:

• Neuroscience
• Medicinal Chemistry
• Pharmacology

Background:

• Glutamate neurotransmission is critical for brain function, primarily mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.
• Transmembrane AMPA receptor regulatory proteins (TARPs) modulate AMPA receptor trafficking and gating, with TARP γ-8 being prevalent in the hippocampus.

Purpose of the Study:

• To discover and optimize negative modulators of AMPA receptors associated with TARP γ-8.
• To develop novel compounds with improved potency and brain penetration for potential therapeutic applications.

Main Methods:

• High-throughput screening was employed to identify initial lead compounds.
• Lead optimization involved structural modifications to enhance potency and mitigate reactive metabolite formation.
• Preclinical characterization included in vivo assessment of target engagement in rats via ex vivo autoradiography.

Main Results:

• A series of 5-arylbenzimidazolone and oxindole-based compounds were synthesized and evaluated.
• Benzimidazolone 3 (JNJ-55511118.1) was identified as a potent modulator.
• Oxindole-based compound 18 demonstrated significant potency (GluA1/γ-8 pIC50 = 9.7) and robust hippocampal target engagement in rats after oral administration.

Conclusions:

• Novel oxindole-based negative modulators of TARP γ-8-associated AMPA receptors were successfully developed.
• Compound 18 represents a promising preclinical candidate with demonstrated efficacy in vivo.
• These findings contribute to the development of therapeutics targeting glutamatergic neurotransmission.