3qi1 | pdb_00003qi1
Design and synthesis of hydroxyethylamine (hea) BACE-1 inhibitors: prime side chromane-containing inhibitors
Structural highlights
Function[BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2] Publication Abstract from PubMedThe 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. Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors.,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, Yednock TA Bioorg Med Chem Lett. 2013 Aug 15;23(16):4674-9. doi: 10.1016/j.bmcl.2013.06.006., Epub 2013 Jun 11. PMID:23856050[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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