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

Summary for 3OHF

• Entry DOI: 10.2210/pdb3ohf/pdb
• Related: 3OHH
• Descriptor: 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)
• Functional Keywords: alzheimer's disease, beta-secretase, memapsin 2, aspartic protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 2
• Total formula weight: 102076.53

Authors

Muckelbauer, J.K. (deposition date: 2010-08-17, release date: 2011-04-06, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)