Imbimbo Bruno P, Del Giudice Elda, Colavito Davide, D'Arrigo Antonello, Dalle Carbonare Maurizio, Villetti Gino, Facchinetti Fabrizio, Volta Roberta, Pietrini Vladimiro, Baroc Maria F, Serneels Lutgarde, De Strooper Bart, Leon Alberta
Research & Development, Chiesi Farmaceutici, via Palermo 26/A, 43100 Parma, Italy.
J Pharmacol Exp Ther. 2007 Dec;323(3):822-30. doi: 10.1124/jpet.107.129007. Epub 2007 Sep 25.
Some nonsteroidal anti-inflammatory drugs has been shown to allosterically modulate the activity of gamma-secretase, the enzymatic complex responsible for the formation of beta-amyloid (Abeta). 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074) is a new gamma-secretase modulator, devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro. We evaluated the effects of chronic CHF5074 treatment on brain Abeta pathology in Tg2576 transgenic mice. Twenty-eight animals of 9.5 to 10.5 months of age received CHF5074-medicated diet (375 ppm) or standard diet for 17 weeks. Compared with controls, CHF5074 treatment significantly reduced the area occupied by plaques and the number of plaques in cortex (-52.2 +/- 5.6%, p = 0.0003 and -48.9 +/- 6.6%, p = 0.0004, respectively) and hippocampus (-76.7 +/- 6.4%, p = 0.004 and -66.2 +/- 10.3%, p = 0.037, respectively). Biochemical analysis confirmed the histopathological measures, with CHF5074-treated animals showing reduced total brain Abeta40 (-49.2 +/- 9.2%, p = 0.017) and Abeta42 (-43.5 +/- 9.7%, p = 0.027) levels. In a human neuroglioma cell line expressing Swedish mutated form of amyloid precursor protein (H4swe), CHF5074 reduced Abeta42 and Abeta40 secretion, with an IC50 of 3.6 and 18.4 microM, respectively, values consistent with those measured in the brain of the CHF5074-treated Tg2576 mice (6.4 +/- 0.4 microM). At 5 microM, no effects were observed on Notch intracellular cleavage in human embryonic kidney 293swe cells. CHF5074 was well tolerated by Tg2576 mice. No abnormal findings were observed upon histopathological examination of the gastrointestinal tract, indicating the absence of COX-related toxicity. Semiquantitative histochemical evaluation of goblet cells in the ileum of vehicle- and CHF5074-treated animals yielded similar results, suggesting no effects on Notch pathway. CHF5074 is therefore a promising therapeutic agent for Alzheimer's disease.
一些非甾体抗炎药已被证明可别构调节γ-分泌酶的活性，γ-分泌酶是负责生成β-淀粉样蛋白（Aβ）的酶复合物。1-(3',4'-二氯-2-氟[1,1'-联苯]-4-基)环丙烷羧酸（CHF5074）是一种新型γ-分泌酶调节剂，在体外无抗环氧化酶（COX）和干扰Notch的活性。我们评估了长期给予CHF5074对Tg2576转基因小鼠脑Aβ病理的影响。28只9.5至10.5月龄的动物接受含CHF5074的饲料（375 ppm）或标准饲料，持续17周。与对照组相比，CHF5074治疗显著减少了皮质中斑块所占面积和斑块数量（分别为-52.2±5.6%，p = 0.0003和-48.9±6.6%，p = 0.0004）以及海马中的斑块所占面积和斑块数量（分别为-76.7±6.4%，p = 0.004和-66.2±10.3%，p = 0.037）。生化分析证实了组织病理学测量结果，接受CHF5074治疗的动物脑内总Aβ40（-49.2±9.2%，p = 0.017）和Aβ42（-43.5±9.7%，p = 0.027）水平降低。在表达瑞典突变形式淀粉样前体蛋白的人神经胶质瘤细胞系（H4swe）中，CHF5074降低了Aβ42和Aβ40的分泌，IC50分别为3.6和18.4 μM，这些值与在接受CHF5074治疗的Tg[2576]小鼠脑中测得的值（6.4±0.4 μM）一致。在5 μM时，未观察到对人胚肾293swe细胞中Notch细胞内切割的影响。Tg2576小鼠对CHF5074耐受性良好。对胃肠道进行组织病理学检查未发现异常，表明不存在COX相关毒性。对给予赋形剂和CHF5074的动物回肠中的杯状细胞进行半定量组织化学评估，结果相似，表明对Notch途径无影响。因此，CHF5074是一种有前景的阿尔茨海默病治疗药物。
