作用于AMPA受体的抗癫痫药吡仑帕奈的研制

新药创制是复杂的智力活动,涉及科学研究、技术创造、产品开发和医疗效果等多维科技活动。每个药物都有自身的研发轨迹,而构建化学结构是最重要的环节,因为它涵盖了药效、药代、安全性和生物药剂学等多维性质。本栏目以药物化学视角,对有代表性的药物的成功构建,加以剖析和解读。癫痫病是难治的中枢神经性疾病,发病机制虽未完全清楚,但已知谷氨酸AMPA受体亚型过分活跃是癫痫发作的重要原因。武田制药公司的抗癫痫药吡仑帕奈就是针对AMPA靶标研制的,研制过程体现了以靶标为核心的理念和实施途径,从发现先导物、结构优化、确定候选化合物,到临床研究和上市,紧密围绕着对靶标的活性和选择性以及化合物的成药性等内容,成功地概念验证了结构优化的合理性。     

发现新药的现状与未来：药物化学的任务

引言药物化学对发现新药所起的作用包括两个主要方面:发觉先导药物(lead detection)和进行优选(Optimization)。发觉先导药物实际上一直是药物化学家的艰巨任务。从理论上和实践上来说,要创制新的先导药物存在着两种可能性:筛选和设计。筛选是将一些多少是随机选择的化合物提供给一项或一组试验,以期发现有用的生物学性质的过程。     

《药物设计策略》书评

科学出版社出版的《药物设计策略》一书是郭宗儒先生继《药物化学总论》和《药物分子设计》著作后的又一本新的力作。前二本著作主要阐述药物化学的基本原理和药物设计的具体方法,本书则从理念和策略上讨论药物分子设计。该书共有10章,内容大致可分为四个部分。第1,2章主要阐述与创新药物研究密切相关的苗头化合物、先导物和候选药     

国外加快新药研发的技术动向

创新药物的研究开发过程正在发生显著变化。国际大制药公司关注综合应用多种新技术以提高效率，缩短周期，减少成本，降低风险。本文叙述国外专家讨论加快新药研发的部分关键技术动向，包括临床前先导物优化技术、候选药选择、分离科学、芯片技术、固态分析、化学和生物学信息联机测定、物理化学性质研究、信息处理等内容。     

基于片段方法创制的药物

小分子药物与靶标的结合大都以非共价键结合,氢键、静电、疏水和范德华作用以维持结合力,这些因素越多结合越牢固,活性越强。但往往伴随分子尺寸变大,产生过膜吸收代谢等药代问题,最终影响成药性。基于片段的药物发现(fragment-based drug discovery, FBDD)是普筛高质量片段以发现苗头分子,结合结构生物学,在片段生长、连接和融合中形成先导物,以及优化出候选物的运行中,始终兼顾化合物活性和物化性质之间的协调性。基于片段的药物发现与基于靶标结构的药物发现存在密切关系。本文以数个上市的药物简释FBDD的应用原理。     

《药物设计策略》书评

<正>科学出版社出版的《药物设计策略》一书是郭宗儒先生继《药物化学总论》和《药物分子设计》著作后的又一本新的力作。前两本著作主要阐述药物化学的基本原理和药物设计的具体方法,本书则从理念和策略上讨论药物分子设计。该书共有10章,内容大致可分为四个部分。第1、2章主要阐述与创新药物研究密切相关的苗头化合物、先导物和候选药物三者之间关系、评价标准、研究方法和策略,构成本书的引言;第3⁵章从药物的宏观性质和微观结构关系入     

《药物设计策略》书评

<正>科学出版社出版的《药物设计策略》一书是郭宗儒先生继《药物化学总论》和《药物分子设计》著作后的又一本新的力作。前两本著作主要阐述药物化学的基本原理和药物设计的具体方法,本书则从理念和策略上讨论药物分子设计。该书共有10章,内容大致可分为四个部分。第1、2章主要阐述与创新药物研究密切相关的苗头化合物、先导物和候选药物三者之间关系、评价标准、研究方法和策略,构成本书的引言;第3⁵章从药物的宏观性质和微观结构关系入     

潜在药靶的发现和验证

潜在药靶的发现与验证是制约新药研究和开发的瓶颈,对于创新药物研究意义重大,且前景广阔。本文主要综述潜在药靶的成药性和特异性、候选化合物的类药性,以及潜在药靶的发现与验证方法及其应用等,对实现从基因到药物的药物创制战略具有一定意义。     

药物代谢研究在新药开发中的作用

新药研究的过程一般可分为药物设计和新药开发两个阶段。药物设计包括:(1)针对某一特定治疗靶点设计先导化合物,(2)根据先导化合物的药理、毒理及代谢等特性进行结构改造以获得新的候选物;在药物开发阶段主要对候选物进行药效及毒性评估。药物代谢研究在这两个阶段都发挥?..     

作用于刺猬信号通路的Smo受体首创性药物格拉德吉

新药创制是复杂的智力活动,涉及科学研究、技术创造、产品开发和医疗效果等多维科技活动。每个药物都有自身的研发轨迹,而构建化学结构是最重要的环节,因为它涵盖了药效、药代、安全性和生物药剂学等多重性质。本栏目以药物化学视角,对有代表性的药物的成功构建,加以剖析和解读。辉瑞公司研制的格拉德吉,是以干扰刺猬信号通路为靶标治疗急性髓性白血病的首创性药物,在多个单位致力于研发Smo受体抑制剂中,成为全球第一个上市的药物。当今处于临床研究状态的Smo抑制剂结构类型归属于两类:天然活性物质环巴胺的类似物和苯并咪唑联苯胺类的合成化合物。本品是以苯并咪唑联苯化合物为先导物,通过改变苯环为哌啶连接基,用构效分析和试错反馈调整分子结构和构象,优化活性-药代-物化性质而成功的。     

Computational techniques in fragment based drug discovery

Fragment based drug discovery is gaining acceptance as a complement to other more established techniques to identify leads and optimize drug candidates. In this review we illustrate areas where fragment based drug discovery has had an impact and point to some examples that show how fragment based analysis is being applied to new arenas. The traditional uses of computational methods in fragment based for lead discovery and optimization and for risk assessment are briefly summarized. The application of fragment analysis for the definition of bioisosteric replacements are discussed together with techniques to characterize the diversity of chemical libraries based on fragment distribution.     

Addressing metabolic activation as an integral component of drug design

Formation of reactive intermediates by metabolism of xenobiotics represents a potential liability in drug discovery and development. Although it is difficult, if not impossible, to predict toxicities of drug candidates accurately, it is prudent to try to minimize bioactivation liabilities as early as possible in the stage of drug discovery and lead optimization. Measurement of covalent binding to liver microsomal proteins in the presence and the absence of NADPH, as well as the use of trapping agents such as glutathione or cyanide ions to provide structural information on reactive intermediates, have been used routinely to screen drug candidates. These in vitro experiments are often supplemented with in vivo covalent binding data in rats. The resulting data are not only used to eliminate potentially risky compounds, but, more importantly, they provide invaluable information to direct the Medicinal Chemistry group efforts to design analogs with less propensity to undergo bioactivation. Select case histories are presented in which this approach was successfully applied at Merck.     

Prediction of oral drug absorption in humans--from cultured cell lines and experimental animals

BACKGROUND: Over the past decade, the use of drug metabolism and pharmacokinetic (DMPK) parameters to optimize selection of candidates for drug development has become one of the primary focuses of research organizations involved in new drug discovery. OBJECTIVE: This review will focus on the feasibility of predicting human absorption using data from a cultured Caco-2 cell system and non-clinical animals. METHODS: In-house Caco-2 permeability data were compared with human absorption data from the literature. Animal absorption data obtained from current literature were also compared with human data. RESULTS/CONCLUSION: Using a combination of rapid in-vivo and in-vitro DMPK screens on a large array of compounds during the lead optimization process has resulted in the streamlined development of compounds that have acceptable DMPK properties. Since it is well recognized that human intestinal absorption cannot be precisely predicted by a single screening assay, it is important to utilize various in-vitro and in-vivo non-clinical studies during lead optimization in drug discovery.     

The structural modification of natural products for novel drug discovery

Introduction: Throughout history, natural products (NPs) have provided a rich source of compounds that have wide applications in the fields of medicine, health sciences, pharmacy and biology. Although naturally active substances are good lead compounds for the discovery of new drugs, most of them suffer from various deficiencies or shortcomings, such as complex structures, poor stability and solubility. Therefore, structural modification of NPs is needed to develop novel compounds with specific properties.

Areas covered: This article presents an overview on the structural modifications of NPs in drug development. The application of multiple classes of NPs to the treatment of conditions such as cancers, infection, Alzheimer’s and diabetes are discussed. This article also reveals that modification of NPs is a versatile approach to explore their mode of actions, which may lead to the discovery of novel drugs.

Expert opinion: NPs are usually described by structural diversity and complexity. The use of isolated NPs as scaffolds for modification is a good approach to drug discovery and development. Despite many limitations associated with NPs, the total synthesis, semisynthetic modification, SAR-based modification, sometimes even a single atom alteration, may lead to the discovery of a novel drug.     

Lead optimization strategies as part of a drug metabolism environment

The rapid increase in the rate at which new chemical entities can be synthesized by medicinal chemists and tested in vitro for potency using high-throughput screening has provided opportunities for lead selection and optimization of thousands of compounds in major pharmaceutical companies. This opportunity coincides with the realization that drug metabolism input at the lead optimization stage is crucial for the development of compounds, with increased likelihood of success when tested in preclinical safety studies and in phase I trials. This has led to new discovery and optimization paradigms, in which drug metabolism is playing an important role.     

A look at ligand binding thermodynamics in drug discovery

Introduction: Drug discovery is a challenging endeavor requiring the interplay of many different research areas. Gathering information on ligand binding thermodynamics may help considerably in reducing the risk within a high uncertainty scenario, allowing early rejection of flawed compounds and pushing forward optimal candidates. In particular, the free energy, the enthalpy, and the entropy of binding provide fundamental information on the intermolecular forces driving such interaction.

Areas covered: The authors review the current status and recent developments in the application of ligand binding thermodynamics in drug discovery. The thermodynamic binding profile (Gibbs energy, enthalpy, and entropy of binding) can be used for lead selection and optimization (binding enthalpy, selectivity, and adaptability).

Expert opinion: Binding thermodynamics provides fundamental information on the forces driving the formation of the drug-target complex. It has been widely accepted that binding thermodynamics may be used as a decision criterion along the ligand optimization process in drug discovery and development. In particular, the binding enthalpy may be used as a guide when selecting and optimizing compounds over a set of potential candidates. However, this has been recently called into question by arguing certain difficulties and in the light of certain experimental examples.     

In silico prediction of human serum albumin binding for drug leads

Introduction: Binding of drugs to human serum albumin (HSA) strongly influences their pharmacokinetic behavior and is associated with drug safety issues, low clearance, low brain penetration, as well as drug-drug interactions. Thus, in silico prediction of HSA binding contributes significantly to the discovery of new drug candidates.

Areas covered: The authors provide a short overview on the principles of HSA binding and the crystal structure of HSA, as well as discussing and analyzing the recent structure- and ligand-based HSA binding models. The authors also present the advantages and limitations of each methodology to construct efficient local or global models and outline the critical structural features contributing to HSA.

Expert opinion: The in silico estimation of drug binding to HSA in early drug discovery contributes to the lead optimization process. Local models are useful for the design of new compounds with reduced HSA binding for a particular target receptor, while real-time quantitative structure-activity relationships or global models combining structure- and ligand-based approaches serve for compound libraries screening. However, research efforts on other important plasma proteins should be strengthened in the perspective to enable predictions of total plasma protein binding for clinical candidates.     

Improving the decision-making process in structural modification of drug candidates: reducing toxicity

The rule of three, relating to activity-exposure-toxicity, presents the single most difficult challenge in the design and advancement of drug candidates to the development stage. Absorption, distribution, metabolism and excretion (ADME) studies are widely used in drug discovery to optimize this balance of properties necessary to convert lead compounds into drugs that are both safe and effective for human patients. Idiosyncratic drug reactions (IDRs; referred to as type B reactions, which are mainly caused by reactive metabolites) are one type of adverse drug reaction that is important to human health and safety. This review highlights the strategies for the decision-making process involving substructures that, when found in drugs, can form reactive metabolites and are involved in toxicities in humans; the tools used to reduce IDRs are also discussed. Several examples are included to show how toxicity studies have influenced and guided drug design. Investigations of reactive intermediate formation in subcellular fractions with the use of radiolabeled reagents are also discussed.     

全新药物设计方法与常用软件及其在抗癌药物设计中的应用

计算机辅助药物设计已普遍应用于药物研发过程,大大加快了药物开发的速度.特别是全新药物设计方法可以用于识别作用于特异性靶点的全新配体结构.全新药物设计常用软件有LUDI,LigBuilder,LeapFrog,SPROUT和SYNOPSIS等,常用方法有片段连接、片段生长、侧链替换和骨架跃迁等.全新药物设计方法在一些抗癌化合物,如纺锤体驱动蛋白抑制剂、血管内皮生长因子抑制剂、亲环蛋白A抑制剂和BRAF抑制剂等的发现方面,已经发挥了重要作用.综述全新药物设计方法与常用软件,并举例讨论其在新型抗癌药物领域中的应用.