2. Academic Validation
  3. 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

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

Affiliation

  • 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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