3IVI

Design and Synthesis of Potent BACE-1 Inhibitors with Cellular Activity: Structure-Activity Relationship of P1 Substituents

Summary for 3IVI

• Entry DOI: 10.2210/pdb3ivi/pdb
• Descriptor: Beta-secretase 1, SULFATE ION, GLYCEROL, ... (5 entities in total)
• Functional Keywords: aspartyl protease, bace-1 inhibitors, alzheimer's disease, structure-based drug design, disulfide bond, glycoprotein, hydrolase, membrane, protease, transmembrane, zymogen
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 3
• Total formula weight: 138719.88

Authors

Pan, H. (deposition date: 2009-09-01, release date: 2010-01-05, Last modification date: 2024-11-20)

Primary citation

Sealy, J.M.,Truong, A.P.,Tso, L.,Probst, G.D.,Aquino, J.,Hom, R.K.,Jagodzinska, B.M.,Dressen, D.,Wone, D.W.,Brogley, L.,John, V.,Tung, J.S.,Pleiss, M.A.,Tucker, J.A.,Konradi, A.W.,Dappen, M.S.,Toth, G.,Pan, H.,Ruslim, L.,Miller, J.,Bova, M.P.,Sinha, S.,Quinn, K.P.,Sauer, J.M.
Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents.
Bioorg.Med.Chem.Lett., 19:6386-6391, 2009

PubMed Abstract: Using structure-guided design, hydroxyethylamine BACE-1 inhibitors were optimized to nanomolar Abeta cellular inhibition with selectivity against cathepsin-D. X-ray crystallography illuminated the S1' residues critical to this effort, which culminated in compounds 56 and 57 that exhibited potency and selectivity but poor permeability and high P-gp efflux.

PubMed: 19811916
DOI: 10.1016/j.bmcl.2009.09.061

Experimental method

X-RAY DIFFRACTION (2.2 Å)