Department of Geriatrics, Center for Aging Brain, Memory Unit, University of Bari, Bari, Italy.
Drugs Aging. 2009;26(7):537-55. doi: 10.2165/11315770-000000000-00000.
In the last decade, advances in understanding the neurobiology of Alzheimer's disease (AD) have translated into an increase in clinical trials assessing various potential AD treatments. At present, drugs used for the treatment of AD only slightly delay the inevitable symptomatic progression of the disease and do not affect the main neuropathological hallmarks of the disease, i.e. senile plaques and neurofibrillary tangles. Brain accumulation of oligomeric species of beta-amyloid (A beta) peptides, the principal components of senile plaques, is believed to play a crucial role in the development of AD. Based on this hypothesis, huge efforts are being made to identify drugs able to interfere with proteases regulating A beta formation from amyloid precursor protein (APP). Compounds that stimulate alpha-secretase, the enzyme responsible for non-amyloidogenic metabolism of APP, are being developed and one of these, EHT-0202, has recently commenced evaluation in a phase II study. The discovery of inhibitors of beta-secretase (memapsin-2, beta-amyloid cleaving enzyme-1 [BACE-1]), the enzyme that regulates the first step of amyloidogenic APP metabolism, has proved to be particularly difficult because of inherent medicinal chemistry issues and only one compound (CTS-21166) has proceeded to clinical testing. Conversely, several compounds that inhibit gamma-secretase, the pivotal enzyme that generates A beta, have been identified, the most advanced being LY-450139 (semagacestat), presently in phase III clinical development. There has been considerable disappointment over the failure of a phase III study of tarenflurbil, a compound believed to modulate the activity of gamma-secretase, after encouraging phase II findings. Nevertheless, other promising gamma-secretase modulators are being developed and are approaching clinical testing. All these therapeutic approaches increase the hope of slowing the rate of decline in patients with AD and modifying the natural history of this devastating disease within the next 5 years.
在过去的十年中，对阿尔茨海默病（AD）神经生物学的理解的进步已转化为对评估各种潜在 AD 治疗方法的临床试验的增加。目前，用于治疗 AD 的药物仅能略微延缓疾病的必然症状进展，而不会影响疾病的主要神经病理学特征，即老年斑和神经原纤维缠结。β-淀粉样蛋白（Aβ）肽寡聚物的脑积累，老年斑的主要成分，被认为在 AD 的发展中起关键作用。基于这一假设，正在进行大量努力以确定能够干扰调节从淀粉样前体蛋白（APP）形成 Aβ的蛋白酶的药物。正在开发刺激α-分泌酶的化合物，该酶负责 APP 的非淀粉样生成代谢，其中一种化合物 EHT-0202 最近已在 II 期研究中进行评估。发现β-分泌酶（膜丝氨酸蛋白酶 2，β-淀粉样蛋白裂解酶-1 [BACE-1]）抑制剂特别困难，因为存在内在的药物化学问题，只有一种化合物（CTS-21166）已进行临床测试。相反，已经确定了几种抑制γ-分泌酶的化合物，γ-分泌酶是生成 Aβ的关键酶，其中最先进的是 LY-450139（semagacestat），目前处于 III 期临床开发阶段。在一项针对 tarenflurbil 的 III 期研究失败后，人们感到非常失望，该化合物被认为可调节γ-分泌酶的活性，但 II 期结果令人鼓舞。尽管如此，其他有前途的γ-分泌酶调节剂正在开发中，并即将进行临床测试。所有这些治疗方法都增加了在 AD 患者中减缓衰退速度并在未来 5 年内改变这种破坏性疾病自然史的希望。
