Innovative Medicines AstraZeneca, CNS and Pain, 15185 Södertälje, Sweden.
J Biol Chem. 2012 Nov 30;287(49):41245-57. doi: 10.1074/jbc.M112.409110. Epub 2012 Oct 9.
β-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid β peptide (Aβ) species. Because cerebral deposition of Aβ species might be critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer (FRET) assay, Aβ and sAPPβ release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in mouse, guinea pig, and non-human primate. Pharmacokinetic/pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduces the levels of Aβ in brain, CSF, and plasma in several preclinical species. It might, therefore, have disease-modifying potential in the treatment of Alzheimer disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.
β-淀粉样前体蛋白裂解酶 1（BACE1）是参与淀粉样前体蛋白（APP）加工和形成淀粉样 β 肽（Aβ）的关键酶之一。由于 Aβ 在脑内的沉积可能对阿尔茨海默病的发病机制至关重要，BACE1 已成为治疗这种疾病的关键靶点。在这里，我们报告了 AZD3839 的发现和全面的临床前特征，AZD3839 是一种有效的人 BACE1 选择性抑制剂。AZD3839 是使用基于片段的筛选和基于结构的设计发现的。在浓度依赖性方式下，AZD3839 在生化荧光共振能量转移（FRET）测定中抑制 BACE1 活性，从修饰和野生型人 SH-SY5Y 细胞和小鼠 N2A 细胞以及从小鼠和豚鼠原代皮质神经元中释放 Aβ 和 sAPPβ。对 BACE2 和组织蛋白酶 D 的选择性分别为 14 倍和 >1000 倍。AZD3839 呈剂量和时间依赖性降低小鼠、豚鼠和非人类灵长类动物的血浆、脑和脑脊液中的 Aβ 水平。小鼠和豚鼠数据的药代动力学/药效学分析表明，AZD3839 在原代皮质神经元中的效力与体内脑效应之间具有良好的相关性。这些结果表明，AZD3839 可有效降低几种临床前物种的脑、CSF 和血浆中的 Aβ 水平。因此，它可能在阿尔茨海默病和相关痴呆症的治疗中具有疾病修饰潜力。基于整体药理学特征及其类药性，AZD3839 已进入人体的 I 期临床试验。
