8-四氢吡喃-2-基色满：高选择性β-淀粉样前体蛋白裂解酶 1（BACE1）抑制剂。
8-Tetrahydropyran-2-yl chromans: highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors.
机构信息
Array BioPharma, 3200 Walnut Street, Boulder, Colorado 80301, United States.
出版信息
J Med Chem. 2014 Dec 11;57(23):10112-29. doi: 10.1021/jm5015132. Epub 2014 Nov 26.
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).
开发了一系列 2,3,4,4a,10,10a-六氢吡喃并[3,2-b]色烯类似物，其对 BACE1 表现出高选择性（>2000 倍），而对组织蛋白酶 D（CatD）则没有活性。研究了三种不同的 Asp 结合部分：螺环酰胍、氨基恶唑啉和氨基噻唑啉，以调节效力、选择性、外排和通透性。基于结构的设计指导，对 P2'和 P3 部分进行了探索。P2'位的甲基提供了构象受限的抑制剂，对 BACE1 具有优异的细胞效力（37-137 nM）和选择性（435 至>2000 倍）。这些努力导致了化合物 59 的出现，其在 60 mg/kg（PO）剂量下可使大鼠 CSF Aβ1-40 降低 69%。
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