4X48

Crystal structure of GluR2 ligand-binding core

4X48 の概要

• エントリーDOI: 10.2210/pdb4x48/pdb
• 関連するPDBエントリー: 4LZ5 4LZ7 4LZ8
• 分子名称: Glutamate receptor 2, GLUTAMIC ACID, ZINC ION, ... (5 entities in total)
• 機能のキーワード: ampa receptor, allosteric modulator, membrane protein
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• 細胞内の位置: Cell membrane; Multi-pass membrane protein: P19491
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 92584.94

構造登録者

Pandit, J. (登録日: 2014-12-02, 公開日: 2015-05-06, 最終更新日: 2024-10-16)

主引用文献

Shaffer, C.L.,Patel, N.C.,Schwarz, J.,Scialis, R.J.,Wei, Y.,Hou, X.J.,Xie, L.,Karki, K.,Bryce, D.K.,Osgood, S.M.,Hoffmann, W.E.,Lazzaro, J.T.,Chang, C.,McGinnis, D.F.,Lotarski, S.M.,Liu, J.,Obach, R.S.,Weber, M.L.,Chen, L.,Zasadny, K.R.,Seymour, P.A.,Schmidt, C.J.,Hajos, M.,Hurst, R.S.,Pandit, J.,O'Donnell, C.J.
The Discovery and Characterization of the alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Potentiator N-{(3S,4S)-4-[4-(5-Cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242).
J.Med.Chem., 58:4291-4308, 2015

PubMed Abstract: A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.

PubMed: 25905800
DOI: 10.1021/acs.jmedchem.5b00300

実験手法

X-RAY DIFFRACTION (1.89 Å)