title: 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.
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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Gardinier
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Gernert
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Porter
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Jon K
authors.initials: JK
authors.lastname: Reel
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Ornstein
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: Spinazze
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: F Craig
authors.initials: FC
authors.lastname: Stevens
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Patric
authors.initials: P
authors.lastname: Hahn
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Hollinshead
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mayhugh
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Jeff
authors.initials: J
authors.lastname: Schkeryantz
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Albert
authors.initials: A
authors.lastname: Khilevich
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Oscar
authors.initials: O
authors.lastname: De Frutos
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gleason
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Akihiko S
authors.initials: AS
authors.lastname: Kato
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Debra
authors.initials: D
authors.lastname: Luffer-Atlas
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Prashant V
authors.initials: PV
authors.lastname: Desai
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Swanson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burris
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Chunjin
authors.initials: C
authors.lastname: Ding
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Heinz
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Need
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Vanessa N
authors.initials: VN
authors.lastname: Barth
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Stephenson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Diseroad
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Tim A
authors.initials: TA
authors.lastname: Woods
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: David
authors.initials: D
authors.lastname: Bredt
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, Indiana 46285 United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Witkin
mesh_terms: D015220:Calcium Channels / Q000378:metabolism*; D055808:Drug Discovery; D057166:High-Throughput Screening Assays; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C521178:CACNG8 protein, human; D015220:Calcium Channels; D018091:Receptors, AMPA