1. Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors.
- Author
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Ng RA, Sun M, Bowers S, Hom RK, Probst GD, John V, Fang LY, Maillard M, Gailunas A, Brogley L, Neitz RJ, Tung JS, Pleiss MA, Konradi AW, Sham HL, Dappen MS, Adler M, Yao N, Zmolek W, Nakamura D, Quinn KP, Sauer JM, Bova MP, Ruslim L, Artis DR, and Yednock TA
- Subjects
- Binding Sites, Cells, Cultured, Ethylamines chemical synthesis, Ethylamines chemistry, Ethylamines pharmacology, Inhibitory Concentration 50, Models, Molecular, Structure-Activity Relationship, Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Chromans chemistry, Drug Design, Enzyme Inhibitors chemical synthesis
- 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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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