1610802-53-3Relevant academic research and scientific papers
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
Gardinier, Kevin M.,Gernert, Douglas L.,Porter, Warren J.,Reel, Jon K.,Ornstein, Paul L.,Spinazze, Patrick,Stevens, Craig,Hahn, Patric,Hollinshead, Sean P.,Mayhugh, Daniel,Schkeryantz, Jeff,Khilevich, Albert,De Frutos, Oscar,Gleason, Scott D.,Kato, Akihiko S.,Luffer-Atlas, Debra,Desai, Prashant V.,Swanson, Steven,Burris, Kevin D.,Ding, Chunjin,Heinz, Beverly A.,Need, Anne B.,Barth, Vanessa N.,Stephenson, Gregory A.,Diseroad, Benjamin A.,Woods, Tim A.,Yu, Hong,Bredt, David,Witkin, Jeffrey M.
, p. 4753 - 4768 (2016)
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.
6-((S)-1--ETHYL)-3H-1,3-BENZOTHIAZOL-2-ONE AS A TARP-GAMMA 8 DEPENDENT AMPA RECEPTOR ANTAGONIST
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Paragraph 0060, (2014/06/11)
A TARP γ8 dependant AMPA receptor antagonist of the formula: its pharmaceutically acceptable salts, uses, and methods for its preparation are described.
