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.

Autor:	Gardinier KM; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Gernert DL; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Porter WJ; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Reel JK; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Ornstein PL; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Spinazze P; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Stevens FC; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Hahn P; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Hollinshead SP; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Mayhugh D; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Schkeryantz J; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Khilevich A; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., De Frutos O; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Gleason SD; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Kato AS; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Luffer-Atlas D; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Desai PV; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Swanson S; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Burris KD; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Ding C; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Heinz BA; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Need AB; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Barth VN; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Stephenson GA; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Diseroad BA; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Woods TA; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Yu H; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Bredt D; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States., Witkin JM; Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2016 May 26; Vol. 59 (10), pp. 4753-68. Date of Electronic Publication: 2016 Apr 29.
DOI:	10.1021/acs.jmedchem.6b00125
Abstrakt:	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.
Databáze:	MEDLINE
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