Design and synthesis of potent hydroxyethylamine (HEA) BACE-1 inhibitors carrying prime side 4,5,6,7-tetrahydrobenzazole and 4,5,6,7-tetrahydropyridinoazole templates |
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Authors: | Christian Sund Oscar Belda Neera Borkakoti Jimmy Lindberg Dean Derbyshire Lotta Vrang Elizabeth Hamelink Cathrine Åhgren Esmeralda Woestenenk Kristina Wikström Anders Eneroth Erik Lindström Genadiy Kalayanov |
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Affiliation: | Medivir AB, Lunastigen 7, SE-14144 Huddinge, Sweden |
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Abstract: | A set of low molecular weight compounds containing a hydroxyethylamine (HEA) core structure with different prime side alkyl substituted 4,5,6,7-tetrahydrobenzazoles and one 4,5,6,7-tetrahydropyridinoazole was synthesized. Striking differences were observed on potencies in the BACE-1 enzymatic and cellular assays depending on the nature of the heteroatoms in the bicyclic ring, from the low active compound 4 to inhibitor 6, displaying BACE-1 IC50 values of 44 nM (enzyme assay) and 65 nM (cell-based assay). |
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Keywords: | Aβ amyloid Alzheimer’s disease β-Secretase BACE-1 inhibition Hydroxylamine (HEA) isostere |
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