3QI1

Design and synthesis of hydroxyethylamine (hea) BACE-1 inhibitors: prime side chromane-containing inhibitors

Summary for 3QI1

• Entry DOI: 10.2210/pdb3qi1/pdb
• Descriptor: Beta-secretase 1, N-[(2S,3R)-4-{[(2R,4S)-2-cyclopropyl-6-(2,2-dimethylpropyl)-3,4-dihydro-2H-chromen-4-yl]amino}-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]acetamide (3 entities in total)
• Functional Keywords: aspartate 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: 1
• Total formula weight: 45895.49

Authors

Yao, N. (deposition date: 2011-01-26, release date: 2012-03-28, Last modification date: 2024-11-20)

Primary citation

Ng, R.A.,Sun, M.,Bowers, S.,Hom, R.K.,Probst, G.D.,John, V.,Fang, L.Y.,Maillard, M.,Gailunas, A.,Brogley, L.,Neitz, R.J.,Tung, J.S.,Pleiss, M.A.,Konradi, A.W.,Sham, H.L.,Dappen, M.S.,Adler, M.,Yao, N.,Zmolek, W.,Nakamura, D.,Quinn, K.P.,Sauer, J.M.,Bova, M.P.,Ruslim, L.,Artis, D.R.,Yednock, T.A.
Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors.
Bioorg.Med.Chem.Lett., 23:4674-4679, 2013

PubMed Abstract: The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.

PubMed: 23856050
DOI: 10.1016/j.bmcl.2013.06.006

Experimental method

X-RAY DIFFRACTION (2.3 Å)