Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka 532-8686, Japan.
J Neurosci. 2010 Aug 18;30(33):11157-66. doi: 10.1523/JNEUROSCI.2884-10.2010.
We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of Abeta peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble Abeta, increased that of neurotrophic sAPPalpha by approximately 20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral Abeta deposition by approximately 60%, preserving the pharmacological efficacy on soluble Abeta and sAPPalpha levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.
我们发现一种非肽类化合物 TAK-070，它以非竞争性方式抑制 BACE1，BACE1 是产生被认为是阿尔茨海默病（AD）病因的 Abeta 肽的限速蛋白酶。TAK-070 与全长 BACE1 结合，但不与缺乏跨膜结构域的截断 BACE1 结合。短期口服 TAK-070 可降低大脑中可溶性 Abeta 的水平，使神经营养性 sAPPalpha 的水平增加约 20%，并使 Tg2576 小鼠（AD 的 APP 转基因小鼠模型）认知测试中的行为障碍正常化。6 个月的慢性治疗可使大脑中的 Abeta 沉积减少约 60%，同时保持对可溶性 Abeta 和 sAPPalpha 水平的药效。这些结果支持使用非竞争性抑制剂抑制 BACE1 作为 AD 的疾病修饰和症状治疗的可行性。
