老药在药物设计中的应用

药物的副作用是由于药物与不希望的靶标发生了作用，这是由于靶标受体与药物分子的杂泛性所致。药物的杂泛性具有双重性：有利的方面是可用于设计多靶标作用药物；不利方面是其所产生的副作用。然而，药物的副作用也可以作为研发新药的出发点，经结构改造消除或减弱原药的主作用，提升某副作用使其成为新的药物。近年来确定的许多药物靶标，为老药的新用途提供了生物学依据。老药已在临床应用，其物化、药代和安全性应有保障，因而研发的起点高，同时副作用也是根据临床观察所见，故依此研发新药的成功几率较高。在分子变换中，重要之点是结构的新颖性和拥有知识产权。     

药物分子设计的策略: 分子的宏观性质与微观结构的统一

药物与机体的相互作用，包含机体对药物的处置和药物对机体的作用。机体对药物的处置，所进行的物理和化学、时间和空间的处置，遵循一般的规律，具有共性特征，即分子的整体和宏观性质影响药代动力学行为。药物对机体的作用，是药物分子与靶标蛋白的物理或化学结合，引发药理(或毒理)作用，起因于药物的特异性作用，是药物分子的个性表现，受制于药物分子中特定的原子或基团与靶标分子在三维空间的结合，这种微观结构就是药效团。药物分子可视作宏观性质与微观结构的集合，统一在分子的整体结构之中，宏观性质决定药代和物化性质，微观结构决定药理作用。认识宏观与微观同药代与药效的内在相互关系，可以深化对药物作用的认识，指导药物分子设计。决定分子宏观性质的因素是相对分子质量、水溶性、电荷、脂溶性(分配性)和极性表面积等，通常是由分子骨架和整体分子所决定，无特异性的结构要求；决定活性的微观结构因素有氢键给体、氢键接受体、正电中心、负电中心、疏水中心和芳环中心。不同的生物活性取决于这些不同特征的组合及其空间排布。分子的宏观性质，包含了微观结构中原子和基团的贡献；在改变分子的结构以调整宏观性质时，往往影响微观结构的空间位置。药物分子设计的技巧是整合这两个因素成最佳配置，在早期研究阶段，应兼顾宏观性质与微观结构，使药效强度和选择性、药代动力学和药物的物理化学性质达到最佳的匹配，为此，要求表征药代的空间与药效学的选择性空间有结构交盖。     

药物分子设计的策略：双靶标药物设计

新药研究可分两种模式：以生理学和表型为基础的研究和以生物靶标为核心的药物研究,这两种模式相互补充和印证。当今以靶标为切入点的模式占主导地位,研发出不少新药。许多疾病如肿瘤、代谢性和中枢神经系统疾病的药物治疗非单一靶标可治愈,同时干预与疾病相关的双（多）靶标药物可提高药物的效力,因而成为创制新药的活跃领域。双靶标药物可以是两个受体的调节剂、两个酶的抑制剂或同时作用于酶和受体或作用于受体和通道或转运蛋白的双功能性分子等。从药物分子设计的视角,构建双靶标药物分子可将两个活性分子或其药效团用连接基连接在一起,构成连接型分子;两个活性分子的部分结构或药效团特征相同,可将共同部分融合或并合,形成融合型或并合型分子,可以控制分子的大小和相对分子质量,使得分子结构的药效空间与药代动力学空间有较大的重叠,提高成药的几率。     

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。     

抗肿瘤药venetoclax的研发和启示

抑制蛋白-蛋白相互作用(PPI)的小分子药物向来是新药研发的难题,雅培公司创制的venetoclax是第一个真正意义上的PPI抑制剂。该药研发20年,历尽曲折与风险。本文从药物化学的视角简要介绍其研发过程。Venetoclax的研制涉及多种技术方法,包括用核磁共振(SAR by NMR),基于片段的药物发现(FBDD),X-射线晶体学指导基于蛋白结构的分子设计以及集中库的设计等。研发中两次更改靶标,由单一的靶标Bcl-x L蛋白改换成双靶标Bcl-x L/Bcl-2,最后聚焦为Bcl-2蛋白,彰显出研发的巨大风险性,见证了确证靶标的可药性(druggability)贯穿于从先导物到临床试验的全过程。作为口服治疗慢性淋巴白血病的药物,Venetoclax的创新性还表现出化学结构突破了"类药5规则"的限制,分子量为882的化合物足以屏蔽掉两个蛋白的结合热域(hot spots)也体现了构建化学结构的成功。     

药物分子设计的策略：论药效团和骨架迁越

药物分子是由药效团和结构骨架构成的，药效团是由不连续的离散的原子、基团或片断所构成，但需结合在分子骨架上，形成具体的分子。骨架具有连续性，相同的药效团附着在不同的分子骨架上，构成了作用于同一靶标而结构多样的化合物。骨架依据受体的柔性和可塑性形成了“杂乱性”的空间。显示了受体结合部位的杂乱性。杂乱性越大，可容纳的配体分子的结构多样性就越多，意味着结构修饰与变换的余地大，成药的机会多。由苗头化合物演化成先导物，进而优化成候选药物，这由化合物变革成安全、有效、稳定、可控的药物过程就是保持药效团、变换分子骨架、修饰基团和边链的过程。结构骨架的变化可分为3个层次：以电子等排原理变换骨架结构；以优势结构为导向变换骨架结构；以结构一活性演化的方式变换骨架结构，即骨架迁越。骨架迁越的目的是改善分子的物化、药代、稳定性和赋予分子的结构新颖性。该文以实例阐述了骨架变换的方法与技巧。     

药物分子设计的策略:药理活性与成药性

化合物的内在活性和成药性是创新药物的两个基本要素,活性是药物的基础和核心,成药性是辅佐活性发挥药效的必要条件,两者互为依存。药物在体内的药剂相、药代动力相和药效相可概括为活性和成药性的展示过程。成药性是药物除活性外的其他所有性质,包括物理化学性质、生物化学性质、药代动力学性质和毒副作用,这是在不同层次上表征药物的性质和行为,但又相互关联与制约。活性与成药性由化学结构所决定,体现在微观结构与宏观性质的结合上,寓于分子的结构之中。先导物的优化是对活性、物化、生化、药代和安全性等性质的多维空间的分子操作,因而具有丰富的药物化学内涵。     

现代生物制药名词解释

<正> 基因组药物 genomic derived drugs 指利用基因序列数据,经生物信息分析,高通量基因表达、高通量功能筛选和体内外药效试验,研究开发得到的新药先导物。其工作程序可简列如下:基因组序列→确定药物靶标→结构测定→三维蛋白质结构→配体接合部位→基于结构配体的设计→新药先导物。人类基因组和蛋白基因组将为新药开发提供大量新靶标。     

结构优化的焓与熵

多参数的先导物优化可归纳为两部分：从微观结构上提高化合物的活性强度和选择性,从宏观性质上优化其物化性质、吸收和药代以及安全性质等,这些集中反映于药理活性和成药性中。内涵于化学结构中的这两部分是相互关联的,例如对靶标的高活性和高选择性的药物可容许物化、代谢和安全性质有更宽泛的表现。药物对靶标的亲和力（如平衡状态下的离解常数Ki）与体外活性（如EC50或IC50）是密切相关的,因而在初期优化中成为衡量化合物质量的主要指标。配体与靶标的亲和力或离解常数可转换为结合自由能,进而可用热力学实验方法将结合能＂化解＂成焓和熵的贡献,这样,在结构优化过程中,测定化合物自由能、焓和熵变,可从原子和基团的性质、取向、位置和距离的变化等更加微观的层面上,理解对活性的影响和量变的规律。配体的这些热力学特征与配体-蛋白复合物的结构生物学特征相结合,可深入揭示配体-受体的结合本质和呈现活性的内涵,从焓-熵的量变中把握结构变换对活性的影响,这是解析药物的作用机制和指导分子设计的有用方法,本文将以实例讨论热力学在结构优化中的应用。     

苯并氮杂?在药物分子设计中的应用及构建

苯并氮杂?是一类由苯环和含氮七元环并联的稠环结构,引入分子中可调节化合物的理化性质,保持或增强化合物的生物活性,还可改善化合物药代性质,提高脑透过性,降低hERG毒性,是药物分子合理设计和结构优化的重要优势骨架。苯并氮杂?结构可通过Dickmann缩合反应、Mitsunobu反应、Pictet-Spengler反应、CMD反应、多组分反应(MCRs)、金属催化、不对称催化等多种方法进行构建,在丰富药物分子结构多样性中发挥重要作用。     

他克莫司药理作用及临床疗效的研究进展

目的:总结他克莫司的药理作用和临床疗效,以期为临床合理使用提供参考。方法:查阅近期国内外相关文献,对他克莫司重要药理作用及疗效、药物相互作用、不良反应进行归纳、总结。结果:他克莫司具有免疫抑制、促神经再生作用,能有效治疗特应性皮炎、类风湿性关节炎、重症肌无力等疾病,与许多药物存在相互作用,可引起神经毒性、心肌增厚、牙龈增生等不良反应。结论:他克莫司临床应用广泛,明确其药理作用及疗效、药物相互作用、不良反应,为临床安全、合理使用提供参考。     

治疗痛风新药非布司他的临床研究进展

痛风是成人常见的炎症性关节炎类型之一。选择性黄嘌呤氧化酶抑制剂非布司他是一种高尿酸血症和痛风治疗新药。本文综述其药动学、作用机制及临床研究。     

Efficiency of Drug Targeting: Steady-State Considerations Using a Three-Compartment Model

Physiological models have often been used to investigate the processes involved in drug targeting. Such a model is used to investigate some aspects of drug targeting, including the pharmacodynamics of therapeutic and toxic effects. A simple pharmacodynamic model is incorporated in a three-compartment pharmacokinetic model. Conventional administration and drug targeting are compared at steady state for the same degree of therapeutic effect. The efficiency of drug targeting is quantified as the ratio (TA) of the rates of administration of free drug or of a drug–carrier complex required to achieve this effect. Also, the ratios of drug concentrations in the toxicity compartment (DTI) or of the consequent degree of toxic effects (TI) are used to compare conventional administration with drug targeting. The kinetic characteristics of the drug–carrier complex, rate of elimination, and rate of free drug release, influence TA but not DTI or TI. The importance of these characteristics depends on the cost and toxicity of the drug–carrier complex or of the carrier alone. The pharmacodynamics of the free drug in both the target and the toxicity compartments have an important influence on TI but not on TA or DTI. As the pharmacological selectivity of the drug increases, so does TI. However, a drug with good pharmacological selectivity may not be suitable for drug targeting. TI is also very dependent on the shape of the effect–concentration curves, particularly that for toxicity. While TA increases as the rate of elimination of free drug from either central or target compartments increases, TI may actually be reduced if release of free drug is not confined to the target compartment.     

Effect of active drug metabolites on plasma level-response correlations

Application of pharmacokinetic principles to patient therapy requires prior elucidation of the relationship between the plasma concentration of a drug and its pharmacological effects. This relationship is complicated by the fact that many drugs are converted to active metabolites so that observed effects represent a composite of the pharmacological activity of a drug and its metabolites. In fact, discrepancies between the observed duration of drug action and the biological half-life of a given drug should suggest that an active drug metabolite may have been formed. As is illustrated by the anticonvulsant drug methsuximide, drug metabolite levels may be so much higher than those of the parent drug that only the metabolite levels are of routine clinical significance. In other cases, levels of both the parent drug and one or more metabolites must be considered together and combined according to their relative potency to give an index of total pharmacological activity. This situation poses obvious difficulties with respect to the ease and safety of drug therapy with these agents. It generally would seem preferable to treat patients with drugs that are converted to inactive metabolites or are excreted largely unchanged.This work was supported in part by grants from the Burroughs Wellcome Foundation and from the National Institute of General Medical Sciences, National Institutes of Health (GM-22371).Presented, in part, at the Swedish Academy of Pharmaceutical Sciences Symposium on Pharmacokinetics and Drug Effects, Stockholm, November 6–8, 1974, and, in abstract form, inActa Pharm. Suecica 11:659 (1974).Burroughs Wellcome Scholar in Clinical Pharmacology.     

Statin drug interactions and related adverse reactions

Introduction: Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Because statins are prescribed on a long-term basis, their possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment.

Areas covered: This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions and related adverse reactions.

Expert opinion: Avoiding drug–drug interactions and consequent adverse drug reactions is essential in order to optimize compliance, and thus improve the treatment of patients at high cardiovascular risk. The different pharmacokinetic profiles among statins should be carefully considered, in order to understand the possible spectrum of drug interactions. The growing trend toward earlier statin treatment for the prevention of cardiovascular disease means that physicians must anticipate future polypharmacy when their patients require additional medications for comorbid conditions.     

改善中药挥发油稳定性的制剂学研究进展

查阅近年来中药挥发油稳定性研究的相关文献，综述改善挥发油稳定性的制剂学进展。中药挥发油药理作用明确，主要采用包合物及微载体技术改善其稳定性，研究手段基于环糊精包合物、微囊、徽乳、脂质体及纳米粒等给药系统。挥发油经微载体包封后，稳定性明显提高，有利于进一步的制剂研制和药效发挥。     

Regulatory considerations on the role of general pharmacology studies in the development of therapeutic agents

In contrast to the well-defined regulatory requirements for the conduct of animal toxicology studies, FDA regulations and guidelines for nonclinical pharmacodynamic studies are relatively general and do not require that any specific studies be conducted. General pharmacology studies are conducted to identify actions of a new agent in addition to those associated with the primary therapeutic utility. General pharmacology studies aimed at determining drug effects on cardiovascular, central nervous system, gastrointestinal, respiratory and pulmonary, renal, endocrine and metabolism, autonomic nervous system, and drug-receptor functions were among the types of general pharmacology studies included in a sample of recent investigational new drug application (IND) and new drug application (NDA) submissions. Assessment of drug effects on cardiovascular, autonomic nervous system, and drug-receptor interactions were given the greatest individual importance in identifying drug effects relevant to the assessment of a product's safety at the initial IND stage. At the NDA stage, general pharmacology studies find their greatest value in predicting drug-drug interactions, defining mechanisms of action, characterizing the pharmacological correlates of drug-overdose, identifying dose-limiting effects for the chronic toxicity studies, and associating animal toxicity findings with known pharmacotoxic effects. General pharmacology studies provide valuable information to complement animal toxicity studies for evaluating a drug's potential risk to humans.     

In Vitro and In Vivo Studies Evaluating a Liposome System for Drug Solubilization

A liposome system was developed which demonstrates suitability as an intravenous drug carrier for a lipophilic drug compound (RS-93522, a dihydropyridine CA²⁺ channel blocker). An aqueous phospholipid suspension was employed as a nontoxic solubilizing vehicle for this drug. The liposome formulation, composed of a 3% mixture of dioleoylphosphatidylcholine and dioleoylphosphatidylglycerol, produced a physically and chemically stable preparation which solubilized the lipophilic drug compound at a concentration 500 times above its intrinsic aqueous solubility. Characterizing the liposome–drug system by gel filtration chromatography showed that the drug comigrated with the lipid constituents of the liposome. Further in vitro studies established that the liposome–RS-93522 formulation allowed for rapid and complete transfer of the drug from the liposome to bind with albumin when added to human serum. In vivo studies with rats were performed in which the pharmacokinetics of the liposomal–RS-93522 system were compared to those of a cosolvent-solubilized RS-93522 solution. This study showed that the pharmacokinetic profiles of the two solutions were identical. All the evidence indicates that a liposome formulation of this type does not alter the distribution of the drug in serum and is, therefore, not likely to affect the intrinsic pharmacological or toxicological parameters of the drug relative to the conventional solvent/excipient-containing formulation. This liposome system demonstrates utility as a biocompatible, nontoxic drug delivery vehicle.     

彝药恒古骨伤愈合剂的药理作用和临床应用

目的 对恒古骨伤愈合剂镇痛抗炎、促进骨分化等药理作用和临床应用情况进行综述,为进一步研究和临床用药选择提供依据。方法 通过大量查阅恒古骨伤愈合剂相关书籍与资料,总结归纳恒古骨伤愈合剂镇痛抗炎、促进骨分化等药理作用和临床应用。结果 恒古骨伤愈合剂是以传统中药材黄芪、人参、红花、三七、杜仲、鳖甲、陈皮、钻地风、洋金花等组成的复方制剂,具有活血益气、补肝肾、消肿止痛、促进骨折愈合等功效。近年来动物实验及临床试验均证实其对骨质疏松、骨折、股骨头坏死、腰间盘突出症等具有显著疗效,临床应用广泛。恒古骨伤愈合剂主要不良事件有消化系统损伤、服药过量导致意识不清等,在停药或对症治疗后均能得到控制。结论 恒古骨伤愈合剂具有多种药理作用,经临床应用证实,其疗效较好。