Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat
Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat
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DOI：
10.1124/jpet.112.199356
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发表时间：
2013-03-01
影响因子：
3.5
通讯作者：
Tong, Gary
中科院分区：
文献类型：
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作者：
Albright, Charles F.;Dockens, Randy C.;Tong, Gary
阿尔茨海默病（AD）病理学的标志是脑淀粉样β-肽（A β）的积累，其由γ-分泌酶介导的淀粉样前体蛋白（APP）的裂解产生。因此，γ-分泌酶抑制剂（GSIs）可能会降低脑A β，并提供了一个潜在的新方法来治疗AD。由于γ-分泌酶也切割Notch蛋白，GSI可能由于干扰Notch信号传导而具有不期望的效果。Avagacestat（BMS-708163）是一种GSI，开发用于选择性抑制APP而非Notch裂解。通过测量A β和人Notch蛋白水平，在细胞培养物中评价Avagacestat对APP和Notch切割的抑制作用。在大鼠、犬和人中，通过测量血浆血液浓度与对脑脊液（CSF）A β水平和Notch相关毒性的影响来评价选择性。Notch相关毒性的测量包括肠道杯状细胞化生、脾脏边缘区耗竭、B细胞减少以及血细胞中Notch调节的毛状和分裂增强子同源物-1表达的变化。在大鼠和犬中，avagacestat急性给药可类似地显著降低CSF A β 40和A β 42水平。在大鼠和犬中长期给药，以及在健康人类受试者中28天单次和多次递增剂量给药引起CSF A β 40的相似剂量依赖性降低。与在细胞培养中测量的137倍选择性一致，我们确定了降低CSF A β水平而不引起Notch相关毒性的avagacestat剂量。我们的结果证明了avagacestat对APP的选择性超过Notch切割，支持进一步评价avagacestat用于AD治疗。
A hallmark of Alzheimer's disease (AD) pathology is the accumulation of brain amyloid beta-peptide (A beta), generated by gamma-secretase-mediated cleavage of the amyloid precursor protein (APP). Therefore, gamma-secretase inhibitors (GSIs) may lower brain A beta and offer a potential new approach to treat AD. As gamma-secretase also cleaves Notch proteins, GSIs can have undesirable effects due to interference with Notch signaling. Avagacestat (BMS-708163) is a GSI developed for selective inhibition of APP over Notch cleavage. Avagacestat inhibition of APP and Notch cleavage was evaluated in cell culture by measuring levels of A beta and human Notch proteins. In rats, dogs, and humans, selectivity was evaluated by measuring plasma blood concentrations in relation to effects on cerebrospinal fluid (CSF) A beta levels and Notch-related toxicities. Measurements of Notch-related toxicity included goblet cell metaplasia in the gut, marginal-zone depletion in the spleen, reductions in B cells, and changes in expression of the Notch-regulated hairy and enhancer of split homolog-1 from blood cells. In rats and dogs, acute administration of avagacestat robustly reduced CSF A beta 40 and A beta 42 levels similarly. Chronic administration in rats and dogs, and 28-day, single- and multiple-ascending-dose administration in healthy human subjects caused similar exposure-dependent reductions in CSF A beta 40. Consistent with the 137-fold selectivity measured in cell culture, we identified doses of avagacestat that reduce CSF A beta levels without causing Notch-related toxicities. Our results demonstrate the selectivity of avagacestat for APP over Notch cleavage, supporting further evaluation of avagacestat for AD therapy.