Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Bioorg Med Chem Lett. 2012 May 1;22(9):3203-7. doi: 10.1016/j.bmcl.2012.03.038. Epub 2012 Mar 17.
Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice.
阿尔茨海默病是一种未满足的主要医学需求，其病理学特征为主要由β-淀粉样蛋白组成的细胞外蛋白斑块。γ-分泌酶是负责形成一系列β-淀粉样肽的细胞途径中的关键酶；其中，Aβ42 被认为是负责疾病神经病理学特征的物质。在此，我们报告了 4,4 二取代哌啶 γ-分泌酶抑制剂，这些抑制剂针对体外细胞效力和体内药代动力学性质进行了优化。关键试剂进一步表征了它们降低 APP-YAC 小鼠模型中脑 Aβ42 产生的能力。该结构系列通常具有不理想的药代动力学特性，但基于假设的先导化合物优化使发现能够降低小鼠脑 Aβ42 产生的γ-分泌酶抑制剂成为可能。
