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

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• 作者：Kevin M. Gardinier ; Douglas L. Gernert ; Warren J. Porter ; Jon K. Reel ; Paul L. Ornstein ; Patrick Spinazze ; F. Craig Stevens ; Patric Hahn ; Sean P. Hollinshead ; Daniel Mayhugh ; Jeff Schkeryantz ; Albert Khilevich ; Oscar De Frutos ; Scott D. Gleason ; Akihiko S. Kato ; Debra Luffer-Atlas ; Prashant V. Desai ; Steven Swanson ; Kevin D. Burris ; Chunjin Ding ; Beverly A. Heinz ; Anne B. Need ; Vanessa N. Barth ; Gregory A. Stephenson ; Benjamin A. Diseroad ; Tim A. Woods ; Hong Yu ; David Bredt ; Jeffrey M. Witkin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4753-4768
• 全文大小：694K
• 年卷期：0
• ISSN：1520-4804

文摘

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.