Department of Pharmacy, Central University of Rajasthan, Bandarsindari, Ajmer, Rajasthan 305817, India; Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382 481, Gujarat, India.
Department of Pharmacy, Central University of Rajasthan, Bandarsindari, Ajmer, Rajasthan 305817, India; Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India.
Bioorg Med Chem. 2022 Nov 15;74:117047. doi: 10.1016/j.bmc.2022.117047. Epub 2022 Oct 8.
Alzheimer's disease (AD) is an irreversible, progressive neurological disorder characterized by amyloid plaques, hyperphosphorylated tau protein (hyper p-tau), neuronal damage, memory loss, etc. Various factors, such as age, lifestyle, family history, environmental factors, and gene mutation, cause AD. BACE-1 is an interesting target to prevent or reverse AD progression. BACE-1 cleaves amyloid precursor protein (APP) into soluble amyloid precursor protein β (sAPPβ) and membrane-bound C-terminal fragment called C99, a rate-limiting step, and C99 is further cleaved by gamma-secretase to generate neurotoxic amyloid β (Aβ). Discovery and development of selective β amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibitors have a great potential for the treatment and maintenance of Alzheimer's disease. In this review, we have compiled literature pertaining to guanidine-based novel BACE-1 inhibitors for the treatment and maintenance of AD. We have also discussed role of BACE-1 substrates, and its crystal structure, BACE-1 inhibitors in the clinical trial, and essential points to overcome challenges associated with selective development of BACE-1 inhibitors. This paper provides valuable information for the design and discovery of selective new BACE-1 inhibitors against other aspartyl protease enzymes to treat AD.
阿尔茨海默病（AD）是一种不可逆的、进行性的神经退行性疾病，其特征是淀粉样斑块、过度磷酸化的 tau 蛋白（hyper p-tau）、神经元损伤、记忆丧失等。年龄、生活方式、家族史、环境因素和基因突变等多种因素都会导致 AD。BACE-1 是预防或逆转 AD 进展的一个有趣的靶点。BACE-1 将淀粉样前体蛋白（APP）切割成可溶性淀粉样前体蛋白 β（sAPPβ）和膜结合的 C 端片段 C99，这是一个限速步骤，C99 进一步被 γ-分泌酶切割生成神经毒性淀粉样 β（Aβ）。选择性β淀粉样前体蛋白裂解酶 1（BACE-1）抑制剂的发现和开发对于阿尔茨海默病的治疗和维持具有巨大的潜力。在这篇综述中，我们汇集了关于胍基新型 BACE-1 抑制剂治疗和维持 AD 的文献。我们还讨论了 BACE-1 底物及其晶体结构、BACE-1 抑制剂在临床试验中的作用，以及克服与选择性开发 BACE-1 抑制剂相关的挑战的要点。本文为设计和发现针对其他天冬氨酸蛋白酶的选择性新型 BACE-1 抑制剂以治疗 AD 提供了有价值的信息。
