Discovery of the First α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent upon Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8

  • J Med Chem. 2016 May 26;59(10):4753-68. doi: 10.1021/acs.jmedchem.6b00125.
Kevin M Gardinier  1 ,  Douglas L Gernert  1 ,  Warren J Porter  1 ,  Jon K Reel  1 ,  Paul L Ornstein  1 ,  Patrick Spinazze  1 ,  F Craig Stevens  1 ,  Patric Hahn  1 ,  Sean P Hollinshead  1 ,  Daniel Mayhugh  1 ,  Jeff Schkeryantz  1 ,  Albert Khilevich  1 ,  Oscar De Frutos  1 ,  Scott D Gleason  1 ,  Akihiko S Kato  1 ,  Debra Luffer-Atlas  1 ,  Prashant V Desai  1 ,  Steven Swanson  1 ,  Kevin D Burris  1 ,  Chunjin Ding  1 ,  Beverly A Heinz  1 ,  Anne B Need  1 ,  Vanessa N Barth  1 ,  Gregory A Stephenson  1 ,  Benjamin A Diseroad  1 ,  Tim A Woods  1 ,  Hong Yu  1 ,  David Bredt  1 ,  Jeffrey M Witkin  1
Affiliations
  • 1. Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
PMID: 27067148 DOI: 10.1021/acs.jmedchem.6b00125
Abstract

Transmembrane AMPA Receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA Receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA Receptor Antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA Receptor Antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (-)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA Receptor antagonists. Compound (-)-25 could be utilized to provide proof of concept for antiepileptic efficacy with reduced motor side effects in patients.

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