3S7M

Pyrazolyl and Thienyl Aminohydantoins as Potent BACE1 Inhibitors

3S7M の概要

• エントリーDOI: 10.2210/pdb3s7m/pdb
• 関連するPDBエントリー: 3S7L
• 分子名称: Beta-secretase 1, (5S)-2-amino-3-methyl-5-[3-(pyridin-3-yl)phenyl]-5-(thiophen-3-yl)-3,5-dihydro-4H-imidazol-4-one (3 entities in total)
• 機能のキーワード: aspartyl protease, disulfide bond, endoplasmic reticulum, endosome, glycoprotein, golgi apparatus, membrane, protease, transmembrane, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P56817
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46789.40

構造登録者

Chopra, R.,Olland, A.,Svenson, K. (登録日: 2011-05-26, 公開日: 2011-08-31, 最終更新日: 2024-11-20)

主引用文献

Malamas, M.S.,Erdei, J.,Gunawan, I.,Barnes, K.,Hui, Y.,Johnson, M.,Robichaud, A.,Zhou, P.,Yan, Y.,Solvibile, W.,Turner, J.,Fan, K.Y.,Chopra, R.,Bard, J.,Pangalos, M.N.
New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: Exploring the S2' region.
Bioorg.Med.Chem.Lett., 21:5164-5170, 2011

PubMed Abstract: The proteolytic enzyme β-secretase (BACE1) plays a central role in the synthesis of the pathogenic β-amyloid in Alzheimer's disease. SAR studies of the S2' region of the BACE1 ligand binding pocket with pyrazolyl and thienyl P2' side chains are reported. These analogs exhibit low nanomolar potency for BACE1, and demonstrate >50- to 100-fold selectivity for the structurally related aspartyl proteases BACE2 and cathepsin D. Small groups attached at the nitrogen of the P2' pyrazolyl moiety, together with the P3 pyrimidine nucleus projecting into the S3 region of the binding pocket, are critical components to ligand's potency and selectivity. P2' thiophene side chain analogs are highly potent BACE1 inhibitors with excellent selectivity against cathepsin D, but only modest selectivity against BACE2. The cell-based activity of these new analogs tracked well with their increased molecular binding with EC(50) values of 0.07-0.2 μM in the ELISA assay for the most potent analogs.

PubMed: 21835615
DOI: 10.1016/j.bmcl.2011.07.057

実験手法

X-RAY DIFFRACTION (2.2 Å)