1. Lead Optimization of 5-Aryl Benzimidazolone- and Oxindole-Based AMPA Receptor Modulators Selective for TARP γ-8
- Author
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Brad M. Savall, Perry Leung, Suchitra Ravula, Brian Lord, Ray Rynberg, Kevin J. Coe, Michael P. Maher, Nicholas I. Carruthers, Kai Wang, David La, Devin M. Swanson, Mark Seierstad, Minh Nguyen, Tatiana Koudriakova, Michael K. Ameriks, Nyantsz Wu, Ziff Jeannie M, Daniel J. Pippel, and Timothy W. Lovenberg
- Subjects
0301 basic medicine ,Organic Chemistry ,Glutamate receptor ,Gating ,AMPA receptor ,Neurotransmission ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,nervous system ,chemistry ,Drug Discovery ,Biophysics ,Excitatory postsynaptic potential ,Oxindole ,Receptor ,030217 neurology & neurosurgery ,Ionotropic effect - Abstract
[Image: see text] Glutamate mediates fast excitatory neurotransmission via ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The trafficking and gating properties of AMPA receptors (AMPARs) can be amplified by transmembrane AMPAR regulatory proteins (TARPs), which are often expressed in localized brain regions. Herein, we describe the discovery, lead optimization, and preclinical characterization of 5-arylbenzimidazolone and oxindole-based negative modulators of AMPARs associated with TARP γ-8, the primary TARP found in hippocampus. High-throughput screen lead 4 was optimized for potency and brain penetration to provide benzimidazolone 3, JNJ-55511118.1 Replacement of the benzimidazolone core in 3 with an oxindole mitigated reactive metabolite formation and led to the identification of 18 (GluA1/γ-8 pIC(50) = 9.7). Following oral dosing in rats, 18 demonstrated robust target engagement in hippocampus as assessed by ex vivo autoradiography (ED(50) = 0.6 mg/kg, plasma EC(50) = 9 ng/mL).
- Published
- 2018
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