BACE inhibitors as potential therapeutics for Alzheimer's disease.
BACE inhibitors as potential therapeutics for Alzheimer's disease.
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DOI：
10.2174/157488907782411783
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发表时间：
2007-11-01
期刊：
影响因子：
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通讯作者：
Kenche, Vijaya B
中科院分区：
文献类型：
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作者：
Evin, Genevieve;Kenche, Vijaya B
大脑中β肽的积累导致阿尔茨海默病（AD）病理特征的淀粉样斑块的形成。可溶性低聚物和原纤维具有神经毒性，它们被认为是阿尔茨海默病神经退行性变的主要原因。β是由前体蛋白通过两个连续的切割步骤产生的，其中涉及β和γ分泌酶，这两种蛋白水解酶代表合理的药物靶点。β -分泌酶被确定为膜锚定的天门汀蛋白酶BACE（或BACE1），并在散发性阿尔茨海默病患者的大脑皮层中被发现升高。在这篇综述中，我们总结了目前BACE抑制剂的开发方法，重点是生物活性化合物和相关专利。最近的报道描述了在转基因小鼠模型的大脑中有效抑制β产生的药物。其中一种药物的I期临床试验已经获得批准，我们可以预期，在不久的将来，BACE抑制剂将为治疗AD提供新的有效疗法。
Accumulation of Abeta peptide in the brain results in the formation of amyloid plaques characteristic of Alzheimer's disease (AD) pathology. Abeta soluble oligomers and protofibrils are neurotoxic and these are believed to be a major cause of neurodegeneration in AD. Abeta is derived from a precursor protein by two sequential cleavage steps involving beta- and gamma-secretases, two proteolytic enzymes that represent rational drug targets. beta-secretase was identified as the membrane-anchored aspartyl protease BACE (or BACE1) and found to be elevated in brain cortex of patients with sporadic Alzheimer's disease. In this review, we summarize current approaches towards the development of BACE inhibitors with focus on bioactive compounds and related patents. Recent reports have described drugs that are effective at inhibiting Abeta production in the brain of transgenic mouse models. The beginning of Phase I clinical trials has been approved for one of them and we can expect that in the near future BACE inhibitors will provide novel effective therapeutics to treat AD.