EnVivo Pharmaceuticals, Inc, 500 Arsenal Street, Watertown, MA 02472, USA.
Mol Neurodegener. 2012 Dec 18;7:61. doi: 10.1186/1750-1326-7-61.
A hallmark of Alzheimer's disease is the presence of senile plaques in human brain primarily containing the amyloid peptides Aβ42 and Aβ40. Many drug discovery efforts have focused on decreasing the production of Aβ42 through γ-secretase inhibition. However, identification of γ-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of γ-secretase to shift Aβ production to favor shorter, less amyloidogenic peptides than Aβ42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called γ-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer's disease.
Here we describe EVP-0015962, a novel small molecule γ-secretase modulator. EVP-0015962 decreased Aβ42 in H4 cells (IC50 = 67 nM) and increased the shorter Aβ38 by 1.7 fold at the IC50 for lowering of Aβ42. AβTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other γ-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a γ-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg) decreased Aβ42 and did not alter AβTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt Aβ deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation) reduced Aβ aggregates, amyloid plaques, inflammatory markers, and cognitive deficits.
EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective γ-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of Aβ42, attenuated memory deficits, and reduced Aβ plaque formation and inflammation in Tg2576 transgenic animals. In summary, these data suggest that γ-secretase modulation with EVP-0015962 represents a viable therapeutic alternative for disease modification in Alzheimer's disease.
阿尔茨海默病的一个标志是人类大脑中存在老年斑，主要含有淀粉样肽 Aβ42 和 Aβ40。许多药物发现工作都集中在通过 γ-分泌酶抑制来减少 Aβ42 的产生。然而，γ-分泌酶抑制剂的鉴定也揭示了基于机制的副作用。一种规避这些副作用的方法是调节 γ-分泌酶，使 Aβ 产生偏向于比 Aβ42 短且淀粉样形成能力低的肽，而不影响酶的整体切割效率。这种方法通常称为 γ-分泌酶调节，似乎更有前景，并导致了用于阿尔茨海默病疾病修饰的新治疗候选物的发展。
本文描述了 EVP-0015962，一种新型小分子 γ-分泌酶调节剂。EVP-0015962 在 H4 细胞中降低了 Aβ42（IC50=67 nM），并在降低 Aβ42 的 IC50 时使较短的 Aβ38 增加 1.7 倍。AβTotal 以及淀粉样前体蛋白的其他羧基末端片段没有改变。EVP-0015962 不会导致其他 γ-分泌酶底物（如 Notch 和 ephrin A4 受体）的积累，而 γ-分泌酶抑制剂会同时降低这两种物质的加工水平。单次口服 EVP-0015962（30mg/kg）可降低 Tg2576 小鼠脑内 Aβ42，并且在没有明显 Aβ 沉积的年龄时，以剂量依赖性方式不改变 AβTotal 肽水平。在 Tg2576 小鼠中，EVP-0015962（20 或 60mg/kg/天的食物配方）的慢性治疗可减少 Aβ 聚集体、淀粉样斑块、炎症标志物和认知缺陷。
EVP-0015962 具有口服生物利用度，在体外和体内均可检测到，是一种有效的、选择性的 γ-分泌酶调节剂。EVP-0015962 在小鼠中耐受性良好，可降低 Aβ42 的产生，减轻记忆缺陷，并减少 Tg2576 转基因动物的 Aβ 斑块形成和炎症。总之，这些数据表明，EVP-0015962 的 γ-分泌酶调节代表了阿尔茨海默病疾病修饰的一种可行的治疗选择。
