β-分泌酶抑制剂的研究进展

β-分泌酶是近年来发现的治疗老年痴呆症的新靶点。抑制β-分泌酶的活性能从上游控制关键致病因素β-淀粉样多肽的生成,从而达到治疗老年痴呆症的目的。该文对β-分泌酶抑制剂的研究进展进行了综述。指出以后的工作重点是进行系统深入的生物体内评价,解决药物透过血脑屏障和生物利用度等问题。     

tetramic和tetronic酸作为β-分泌酶抑制剂

阿尔茨海默病（AD）是一种与年龄相关的神经退行性疾病，在工业化城市人群中患病率约2％，65岁以上和85岁以上人群患病率大约分别为10％和50％，且目前并无有效治疗手段。     

γ-分泌酶抑制剂的研发现状

β淀粉样蛋白沉积是阿尔茨海默病的主要病理特征之一，β淀粉样蛋白是经β和卜分泌酶水解口淀粉样蛋白前体蛋白而产生，故β和γ-分泌酶是β淀粉样蛋白前体蛋白代谢的关键性酶，因而成为治疗阿尔茨海默病的很有潜力的靶点。根据β淀粉样蛋白前体蛋白的代谢、β淀粉样蛋白的形成过程及γ-分泌酶的结构、特性和作用机制，分类综述γ-分泌酶抑制剂抑制β淀粉样蛋白前体蛋白的活性及构效关系。     

基于分子片段药物发现技术的β-分泌酶抑制剂研究进展

β-分泌酶抑制剂是开发新型阿尔茨海默病治疗药物的重要研究方向,基于分子片段的药物发现技术是近年来发展的一种基于靶标的药物研究策略。本文综述了近年来利用这一技术发现β-分泌酶抑制剂的研究进展。     

β-内酰胺酶抑制剂合剂的最新研究进展

β-内酰胺酶抑制剂(BLI)在应对革兰阴性菌对β-内酰胺类抗生素的耐药性方向发挥着重要作用,但其疗效因β-内酰胺酶的演进而不断减弱.随着β-内酰胺酶种类以及革兰阴性耐药菌的逐年增加,研发新型BLI及其合剂势在必行.本文对二氮杂双环[3.2.1]辛酮(DBO)和有机硼酸等非β-内酰胺类BLI以及新批准上市和处于不同临床研究阶段的各种BLI合剂进行了较全面的综述.     

羟亚乙基拟肽类人β-分泌酶抑制剂的合成和活性

本文设计并合成了一系列含Leu*Ala羟亚乙基二肽电子等排体的β-分泌酶拟肽类抑制剂,并测定了β-分泌酶抑制活性.活性最强的化合物N9显示59.66％(10 mg/mL)抑制率.化合物N9可经计算化学方法进一步优化.     

与Aβ相关的分泌酶及其在药物设计中的意义

从分子生物学的角度综述了β淀粉样蛋白及其相关的β-分泌酶和γ-分泌酶在阿尔茨海默病发病机制中的作用，并对近年来有关的研究成果在治疗阿尔茨海默病的新药设计中的意义进行了介绍，以期为治疗阿尔茨海默病的药物研发提供思路。     

β-内酰胺酶抑制剂研究进展

自上世纪40年代使用第一个β-内酰胺类抗生索青霉素以来，由于众多该类抗生素的滥用，细菌对其耐药性已成为临床治疗的一大威胁。β-内酰胺酶的产生是细菌对该类抗生素产生耐药的主要机制。为了战胜疾病，人类使川近似剂来克服β-内酰胺酶的破坏作用，使β-内酰胺酶失去活力，这就是近10年来发现的β-内酰胺酶抑制剂。按照作用机理分类．这些抑制剂可分为竞争性和非竞争性两类，其中竞争性抑制剂按其作用性质分为可逆性和不可逆性两类。     

超广谱和耐酶抑制剂β-内酰胺酶的研究进展

产超广谱和耐酶抑制剂β-内酰胺酶是革兰阴性菌对β-内酰胺类抗生素耐药的重要原因。近几十年,这些酶的种类迅速增加,掌握它们的分类、构效关系和耐药模式等方面的知识,对临床合理使用抗生素和防止耐药菌的产生具有重要意义。对超广谱和耐酶抑制剂β-内酰胺酶的最新分类,它们水解β-内酰胺类抗生素的主要结构特点,及其氨基酸位点突变对构效关系的影响进行了介绍。     

XIAP抑制剂的研究进展

凋亡抑制蛋白（XIAP）被认为是凋亡抑制蛋白家族中对细胞凋亡抑制作用最强的蛋白，研究发现。它在许多肿瘤细胞中有过量表达，其作用机制是XIAP对执行凋亡的caspase家族蛋白产生抑制作用。近年来，XIAP小分子抑制剂研究越来越受到人们的重视。该文对XIAP抑制剂的研究进行综述。     

脂肪酸结合蛋白4小分子抑制剂研究进展

存在于脂肪细胞和巨噬细胞中的脂肪酸结合蛋白4(FABP4)能够调节炎症和新陈代谢。研究表明,脂肪酸结合蛋白与新陈代谢综合征、炎症、动脉粥样硬化等疾病的发生存在密切联系。FABP还能够提高胰岛素的敏感性,因而也是治疗2型糖尿病的潜在靶标。本文从化学结构、生物活性、选择性以及构效关系等方面对目前已报道的FABP4小分子抑制剂的研究进行综述。     

Progress toward the discovery and development of efficacious BACE inhibitors

BACE (beta-site amyloid precursor protein [APP] cleavage enzyme) is a transmembrane aspartyl protease responsible for the first cleavage event in the processing of APP to Abeta peptide. Amyloid plaques composed of Abeta peptides are hypothesized to be the root cause of neuronal cell death in Alzheimer's disease patients. Thus, BACE has become a target of significant interest for pharmaceutical and academic research. The recent literature relating to the discovery and development of efficacious BACE inhibitors is reviewed with particular emphasis on the patent literature.     

Conformationally controlled mechanistic aspects of BACE 1 inhibitors

This study highlights conformationally controlled mechanistic aspects of peptide inhibitors for BACE 1. Peptide inhibitors with reduced molecular weight tend to have cyclic conformation leading to reduced interactions with catalytic motif. Conformation plays a major role in determining potency of peptide inhibitors. An attempt has been made at designing lead compound with reduced molecular weight along with proper conformation suitable for active site and retention of specificity analogous to natural substrate. Reduced molecular weight should hopefully lead to enhanced bioavailability.     

Development of BACE1 inhibitors for Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The production and accumulation of beta-amyloid peptides (Abeta) from the beta-amyloid precursor protein (APP) are believed to play a key role in the onset and progression of AD. BACE1 (beta-site APP cleaving enzyme 1) is the protease responsible for the N-terminal cleavage of APP leading to the production of Abeta peptides and the development of BACE1 inhibitors as potential therapeutic agents for AD has generated tremendous interests from both academia and the pharmaceutical industry. A wide variety of BACE1 inhibitors have been reported, several of which have demonstrated highly promising efficacy in animal models of AD. This review focuses on recent disclosures of BACE1 inhibitors in the patent and scientific literature, covering the period from approximately May 2004 to November 2005.     

苯甲脒类BACE1抑制剂的设计和合成(英文)

本文通过对已有小分子库进行虚拟筛选, 得到了可与BACE1活性中心Asp228、Asp32形成氢键作用的苯甲脒片段, 并在其基础上, 设计出了3-苯乙基苯甲脒类BACE1抑制剂。虽然活性测试结果显示这些化合物对BACE1的抑制活性较弱, 但是可以通过进一步的结构优化3-苯乙基苯甲脒类化合物来提高对BACE1的抑制活性。     

Design and synthesis of 2-aminobenzimidazoles as potential BACE1 inhibitors

Fragment-based drug discovery (FBDD) has been widely applied in the research of aspartyl protease inhibitors. In the present study, we reported our work on 2-aminobenzimidazole as the original fragment, which was predicted to bind with the catalytic aspartyl dyad (Asp228 and Asp32) of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). A series of novel 2-aminobenzimidazole derivatives were designed and synthesized. The results from FRET assay revealed that three out of the 12 designed 2-aminobenzimidazoles could inhibit more than 50% of the enzymatic potency of BACE1 at 10 μM. Docking study showed that 2-aminobenzimidazole could form multiple hydrogen bonds and occupy S1/S2’ pockets well.     

Human beta-secretase (BACE) and BACE inhibitors: progress report

A key step in the processing of the integral membrane protein APP, or Amyloid Precursor Protein is through the proteolytic cleavage by the enzyme beta-Secretase (BACE). The proteolysis of APP by BACE, followed by subsequent C-terminal cleavage(s) by gamma-secretase, results in the formation of the amyloid beta (Abeta) peptide. The principal component of the neuritic plaque found in the brains of Alzheimer's Disease (AD) patients is Abeta which is a neurotoxic and highly aggregatory peptide segment of APP. The amyloid hypothesis holds that the neuronal dysfunction and clinical manifestation of AD is a consequence of the long term deposition and accumulation of 40-42 amino-acid long Abeta peptides, and that this process leads to the onset and progression of AD. Due to the apparent causal relationship between Abeta and AD, the so-called "secretases" that produce Abeta have been targeted for development of inhibitors that might serve as therapeutic agents for treatment of this dreaded, and ever more prevalent disease. Herein will be discussed our current understanding of BACE, its role in the formation of neuritic plaques and the known inhibitors of the enzyme.     

Serotonin derivatives as inhibitors of beta-secretase (BACE 1)

All serotonin derivatives described here (1-9) inhibited BACE 1 in a dose dependent manner. The 50% Inhibition Concentration (IC50) of N-cinnamoyl serotonin (1) was 86.7 +/- 4.0 microM. The peptide conjugation of serotonin derivatives influenced the BACE 1 inhibitory activity. Among serotonin derivatives (1-8), introduction of substituents, such as hydroxyl and methoxy groups at the 4'-position decreased the inhibitory activity (N-p-coumaroyl serotonin (2), N-p-methoxy cinnamoyl serotonin (3)). With a hydroxylgroup at the 4'-position, and the meta-hydroxy function being substituted by a hydroxyl group or methoxy group (N-caffeoyl serotonin (4), N-feruloyl serotonin (5)), inhibitory activity was weakened, (IC50 >400 microM). BACE 1 inhibitory activity was effected by the substituents of the cinnamic acid moiety. This is the first report on Structure-Activity-Relationships (SAR) for the BACE 1-inhibiting activity of serotonin derivatives. These serotonin derivatives, which have anti-oxidative effects as well are expected to be useful in the study of the mechanisms of Alzheimer's disease.