Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor
Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor
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DOI：
10.1523/jneurosci.3647-11.2011
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发表时间：
2011-11-16
影响因子：
5.3
通讯作者：
Audia, James E.
中科院分区：
文献类型：
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作者：
May, Patrick C.;Dean, Robert A.;Audia, James E.
根据淀粉样级联假说，脑内淀粉样β蛋白(Aβ)的沉积在阿尔茨海默病(AD)的发病机制中起关键作用。当β-分泌酶(BACE1)裂解淀粉样前体蛋白时，就会产生β-蛋白。十多年来，BACE1一直是设计预防或治疗AD药物的首要目标。然而，事实证明，这类药物的开发具有极大的挑战性，在细胞渗透、口服生物利用度/代谢清除和脑通路方面存在主要障碍。使用基于片段的化学策略，我们已经产生了LY2811376BACE1[[(S)-4-(2，4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5，6-dihydro-4H-[1，3]]，这是第一种口服使用的非肽类BACE1抑制剂，在动物身上产生了深刻的Aβ降低效应。在临床前动物模型中获得的生物标记物变化在健康志愿者中安全和耐受性良好的LY2811376剂量下转化为人。在口服30或90毫克LY2811376后，腰椎脑脊液中显著且持续的Aβ降低被测量到。这是BACE1驱动的中枢神经系统生物标记物变化从临床前动物模型到人类的第一次翻译。由于长期临床前研究中发现的毒理学结果，这种化合物不再在临床开发中取得进展。然而，BACE1仍然是一个可行的靶点，因为这里报告的不良反应是在LY2811376治疗的BACE1 KO小鼠中总结的，因此与BACE1抑制无关。通过抑制BACE1可获得的中枢Aβ还原的幅度和持续时间，将这种蛋白酶定位为一个容易处理的小分子靶点，通过它来检验人类的淀粉样蛋白假说。
According to the amyloid cascade hypothesis, cerebral deposition of amyloid-beta peptide (A beta) is critical for Alzheimer's disease (AD) pathogenesis. A beta generation is initiated when beta-secretase (BACE1) cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 [(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,3] thiazin-2-ylamine], the first orally available non-peptidic BACE1 inhibitor that produces profound A beta-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting A beta reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central A beta reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.