8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors
Journal of Medicinal Chemistry2014Vol. 57(23), pp. 10112–10129
Citations Over TimeTop 16% of 2014 papers
Allen A. Thomas, Kevin W. Hunt, Brad Newhouse, Ryan J. Watts, Xingrong Liu, Guy Vigers, Darin Smith, Susan P. Rhodes, Karin Brown, Jennifer Otten, Michael Burkard, April Cox, Mary Geck, Darrin Dutcher, Sumeet Rana, Robert Kirk DeLisle, Kelly Regal, Albion D. Wright, Robert D. Groneberg, Jiangpeng Liao, Kimberly Scearce‐Levie, Michael Siu, Hans E. Purkey, Joseph P. Lyssikatos
Abstract
A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Aβ1-40 at 60 mg/kg (PO).
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