3OHF

Crystal structure of beta-site app-cleaving enzyme 1 (BACE-WT) complex with bms-655295 aka n~3~-((1s,2r)-1- benzyl-2-hydroxy-3-((3-methoxybenzyl)amino)propyl)-n~1~, n~1~-dibutyl-1h-indole-1,3-dicarboxamide

3OHF の概要

• エントリーDOI: 10.2210/pdb3ohf/pdb
• 関連するPDBエントリー: 3OHH
• 分子名称: Beta-secretase 1, N~3~-{(1S,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-N~1~,N~1~-dibutyl-1H-indole-1,3-dicarboxamide, IODIDE ION, ... (5 entities in total)
• 機能のキーワード: alzheimer's disease, beta-secretase, memapsin 2, aspartic protease, 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: 2
• 化学式量合計: 102076.53

構造登録者

Muckelbauer, J.K. (登録日: 2010-08-17, 公開日: 2011-04-06, 最終更新日: 2024-10-16)

主引用文献

Marcin, L.R.,Higgins, M.A.,Zusi, F.C.,Zhang, Y.,Dee, M.F.,Parker, M.F.,Muckelbauer, J.K.,Camac, D.M.,Morin, P.E.,Ramamurthy, V.,Tebben, A.J.,Lentz, K.A.,Grace, J.E.,Marcinkeviciene, J.A.,Kopcho, L.M.,Burton, C.R.,Barten, D.M.,Toyn, J.H.,Meredith, J.E.,Albright, C.F.,Bronson, J.J.,Macor, J.E.,Thompson, L.A.
Synthesis and SAR of indole-and 7-azaindole-1,3-dicarboxamide hydroxyethylamine inhibitors of BACE-1.
Bioorg.Med.Chem.Lett., 21:537-541, 2011

PubMed Abstract: Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Aβ levels, but did not lower rat brain Aβ due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1.

PubMed: 21078556
DOI: 10.1016/j.bmcl.2010.10.079

実験手法

X-RAY DIFFRACTION (2.1 Å)