β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease that plays a key role in the production of amyloid β (Aβ) in the brain and has been extensively pursued as a target for the treatment of Alzheimer’s disease (AD). BACE2, an aspartyl protease that is structurally related to BACE1, has been recently reported to be involved in melanosome maturation and pigmentation. Herein, we describe the development of a series of cyclopropylthiazines as potent and orally efficacious BACE1 inhibitors. Lead optimization led to the identification of 20, a molecule with biochemical IC₅₀ BACE2/BACE1 ratio of 47. Administration of 20 resulted in no skin/fur color change in a 13-day mouse hypopigmentation study and demonstrated robust and sustained reduction of CSF and brain Aβ₄₀ levels in rat and monkey pharmacodynamic models. On the basis of a compelling data package, 20 (AM-6494) was advanced to preclinical development.

中文翻译：

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AM-6494的发现：一种有效且口服有效的β-位淀粉样前体蛋白裂解酶1（BACE1）抑制剂，对BACE2具有体内选择性。

β-位淀粉样蛋白前体蛋白裂解酶1（BACE1）是一种天冬氨酰蛋白酶，在大脑中淀粉样蛋白β（Aβ）的产生中起关键作用，并已被广泛用作治疗阿尔茨海默氏病（AD）的靶标。最近报道，BACE2是一种与BACE1在结构上相关的天冬氨酰蛋白酶，它参与了黑素体的成熟和色素沉着。在本文中，我们描述了一系列环丙基噻嗪作为有效的和口服有效的BACE1抑制剂的发展。铅的优化导致鉴定出20，一个生化IC ₅₀ BACE2 / BACE1比值为47的分子。施用20在一项为期13天的小鼠色素沉着研究中未导致皮肤/皮毛颜色变化，并在大鼠和猴的药效学模型中证明了CSF和脑_Aβ40水平的稳定持续降低。在引人注目的数据包的基础上，将20（AM-6494）推进了临床前开发。