8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors
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- 作者：Allen A. Thomas ; Kevin W. Hunt ; Brad Newhouse ; Ryan J. Watts ; Xingrong Liu ; Guy Vigers ; Darin Smith ; Susan P. Rhodes ; Karin D. Brown ; Jennifer N. Otten ; Michael Burkard ; April A. Cox ; Mary K. Geck Do ; Darrin Dutcher ; Sumeet Rana ; Robert K. DeLisle ; Kelly Regal ; Albion D. Wright ; Robert Groneberg ; Jiangpeng Liao ; Kimberly Scearce-Levie ; Michael Siu ; Hans E. Purkey ; Joseph P. Lyssikatos
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：December 11, 2014
- 年：2014
- 卷：57
- 期：23
- 页码：10112-10129
- 全文大小：695K
- ISSN：1520-4804
文摘
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鈥?and P3 moieties were explored. A conformationally restricted P2鈥?methyl group provided inhibitors with excellent cell potency (37鈥?37 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 A尾1鈥?0 at 60 mg/kg (PO).