Accumulation of Aβ peptides is a hallmark of Alzheimer’s disease (AD) and is considered a causal factor in the pathogenesis of AD. β-Secretase (BACE1) is a key enzyme responsible for producing Aβ peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration. Starting from a 1,3-dihydrooxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a pK_a lowering strategy to reduce the P-gp efflux and the high hERG potential leading to the discovery of 15 that produced significant Aβ reduction with long duration in pharmacodynamic models and exhibited wide safety margins in cardiovascular safety models. This compound improved the brain-to-plasma ratio relative to 6 by reducing P-gp recognition, which was demonstrated by a P-gp knockout mouse model.

中文翻译：

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新型基于1,3-恶嗪的β-分泌酶（BACE1）抑制剂的合理设计：引入双键以减少P-gp外排，导致大脑中Aβ的强烈降低。

Aβ肽的积累是阿尔茨海默氏病（AD）的标志，并且被认为是AD发病机理的病因。β-分泌酶（BACE1）是负责产生Aβ肽的关键酶，因此抑制BACE1的药物应对AD的疾病缓解治疗有益。在这里，我们描述了通过结合双键降低with碱度并改善脑渗透性来发现和优化新型基于恶嗪的BACE1抑制剂。从1,3-二氢恶嗪开始铅6受了重创到铅SAR以下HTS鉴定，我们通过AP ķ_一个降低的策略，以减少P-gp的外排和高的hERG潜在导致的发现15在药效学模型中，Aβ的降低与持续时间的持续时间相当长，并且在心血管安全性模型中显示出较宽的安全裕度。通过降低P-gp识别，该化合物相对于6改善了脑浆比。P-gp敲除小鼠模型证明了这一点。