新药研发中的me-too, me-better, me-new

文中根据作者对我国新药研发的认识和理解,提出了新药研发过程中me-too,me-better和me-new类新药的概念,并对新药研发过程中的这3类创新活动之间的关系、新药研发的创新程度与经济效益的关系,以及目前我国新药研发的途径选择做了简要的论述。     

口服固体制剂仿制药物疗效的影响因素

目的总结近年来影响仿制药物疗效的因素。方法分析评述近年来的国内外相关文献资料。结果分析影响仿制药物疗效的3个主要因素,包括原料药的优劣及药物晶型、药物制剂和生物活性评价方法。其中,药物制剂和药物晶型是药物质量标准不可控的2个重要因素。结论为提高仿制药物的质量及质量标准提供参考。     

Competitiveness in follow-on drug R&D: a race or imitation?

The development of 'follow on' or 'me too' drugs - generally defined as a drug with a similar chemical structure or the same mechanism of action as a drug that is already marketed - has attracted contrasting views. Some have argued that follow-on drugs often provide useful alternative or enhanced therapeutic options for particular patients or patient subpopulations, as well as introducing price competition. Others, however, consider that the development of such drugs is duplicative and that the resources needed would be better directed elsewhere. Implicit in some of this criticism is the notion that the development of me-too drugs is undertaken after a first-in-class drug has made it to market and proved commercially successful. In this Perspective, using analysis of development and patent filing histories of entrants to new drug classes in the past five decades, we provide new evidence that the development of multiple new drugs in a given class is better characterized as a race, rather than the imitation of successful products.     

药物经济学与“me -too”药物研发

目的:探讨药物经济学如何应用于"me -too"药物研发过程中。方法:首先探讨"me -too"药物目前所处的境况,即对"me -too"药物研发的优势和可能付出的代价进行分析,指出药物经济学研究在"me -too"药物研发过程中应用的必要性,并阐述药物经济学在"me -too"药物研发过程中的应用阶段,应用时如何进行方法的选取及应用时可能出现的问题与对策。结果与结论:药物经济学能够促进"me -too"药物研发的合理性。     

国际药品定价理论与实践对我国药品定价的启示

目的:为我国制定药品价格提供借鉴。方法:分析国际药品价格制定的基本思路和做法,剖析价格制定过程中的难点,探讨国家间价格影响的途径和程度。结果与结论:从市场角度和成本角度设定的价格上线和下线决定了价格的可行范围,将新药额外价值定量化是新药价格制定的关键。我国应该对创新药品和仿制药品分别管理,对创新药品要求提供药物经济学评价来定量化额外价值,对仿制药品实行参考价格体系。     

Fda's Role in the Facilitation of Development of Medical Foods for Rare Conditions: Interactions with Industry

Abstract

In 1984 the Drug Price Competition and Patent Term Restoration Act changed the regulatory climate for generic drugs. This law allowed for the approval of generic «me-too’ copies of many approved drug after the patent had expired. Although the road has not been smooth, the generic drug approval process has had a significant impact on the availability of generic versions of approved drug. This article discusses the evolution and changes that have occurred in generic drug approvals since the 1984 Act.     

基于经典天然产物的药物发现研究

利用现代细胞生物学、分子生物学技术开展经典天然产物的分子机制研究, 建立合适的体外活性评价模型系统, 然后通过药物化学技术进一步研究其结构与活性、结构与毒性、结构与ADME (absorption, distribution, metabolism and excretion) 性质的关系, 是我国发现具有自主知识产权新药的一条有效途径。     

Recent developments with boron as a platform for novel drug design

ABSTRACT

Introduction: After decades of development, the medicinal chemistry of compounds that contain a single boron atom has matured to the present status of having equal rights with other branches of drug discovery, although it remains a relative newcomer. In contrast, the medicinal chemistry of boron clusters is less advanced, but it is expanding and may soon become a productive area of drug discovery.

Areas covered: The author reviews the current developments of medicinal chemistry of boron and its applications in drug design. First generation boron drugs that bear a single boron atom and second generation boron drugs that utilize boron clusters as pharmacophores or modulators of bioactive molecules are discussed. The advantages and gaps in our current understanding of boron medicinal chemistry, with a special focus on boron clusters, are highlighted.

Expert opinion: Boron is not a panacea for every drug discovery problem, but there is a good chance that it will become a useful addition to the medicinal chemistry tool box. The present status of boron resembles the medicinal chemistry status of fluorine three decades ago; indeed, currently, approximately 20% of pharmaceuticals on the market contain fluorine. The fact that novel boron compounds, especially those based on abiotic polyhedral boron hydrides, are currently unfamiliar could be advantageous because organisms may be less prone to developing resistance against boron cluster-based drugs.     

Drug Repurposing and the Medicinal Chemist

Drug repurposing is an approach to finding new uses for older drugs and has been gaining popularity in recent years. The role of traditional medicinal chemistry in the context of these efforts is considered.Every practicing medicinal chemist labors under an assumption that is almost never stated out loud: not all potentially useful drugs for human use have yet been found. It certainly seems like a reasonable viewpoint, given the number of medical conditions either for which there is no pharmacotherapy available or for which existing treatments leave much to be desired. However, another way of addressing this need has gained steam in recent years. “Drug repurposing” is the practice of looking for new clinical uses of existing drugs, which contrasts sharply from de novo drug discovery approaches to therapeutics. The purpose of this essay will be to consider this approach, contrast it to traditional medicinal chemistry, and consider how the two approaches could positively complement each other.The primary concern of all who engage in applied biomedical research should be helping patients in the absence of disciplinary bias. For the medicinal chemist, this means that the goal is to identify the best drug regardless of provenance or commercial concerns (including the recognition that drug therapy itself is not always the best course of action). Of course, pragmatic compromises must usually be considered, whether scientific or economic in nature. “Best” has a temporal connotation as well: the “best” drug today can change as new agents are introduced or as new information is obtained in and beyond clinical trials. For example, there are numerous conditions for which patients would gladly accept an imperfect cure, especially if one does not presently exist. In such cases, the lives of those who suffer improve to some degree, immediately. The state-of-the-art therapies in such areas as Alzheimer’s or Parkinson’s disease, as well as many types of cancer, can very much be viewed in this way. Attaining such a status quo does not mean that all research toward better treatments will stop. To the contrary, this is one area where the self-correcting nature of science flowers best, as scientists and clinicians work together to build a better tomorrow on top of yesterday’s achievements.One of the hardest parts of a de novo drug discovery campaign is starting out, in part due to the challenges of selecting and establishing initial structure–activity relationships on a given chemical series to explore. The short-term assessment of chemical series may be relatively easy to uncover through the selection of appropriate assays and biological models selection, but selecting the right series—i.e., one able to surmount all of the hurdles between discovery chemistry and the clinic—is much harder for the nonclairvoyant. Conventional wisdom has deemed most of the innovations meant to increase passage from early- to late-stage drug discovery wanting, especially the coupling of combinatorial chemistry with high-throughput screening.¹ Although the idea that combinatorial chemistry or any other individual approach has failed is debatable, one thing that everyone can agree on is that it is harder than ever to develop a new drug and that these challenges have negatively impacted the global pharmaceutical enterprise.Enter drug repurposing.Generically, drug repurposing is a collection of approaches that collectively seek to adapt the current pharmacopeia for new uses.²⁻⁴ Included in the complicated taxonomy that is being developed for such approaches⁵ is “drug rescue”, in which promising compounds that have been developed for one indication but have failed to reach the clinic are redirected toward another. For the purposes of this discussion, I will not attempt to differentiate between different flavors of drug repurposing but consider the concept in broad strokes.The proponents of drug repurposing cite numerous scientific advantages of the idea. To my mind, foremost among these is related to a prime challenge in moving a molecule discovered by target-centric biology forward, namely establishing the validity of a new biological target in the treatment of disease. In this view, a considerable amount of time may be saved, as clinical trials would have been facilitated by the fact that the fictional repurposed candidate would have already been approved for use in humans. Other advantages attributed to repurposed drugs accrue from the fact that so much is known about them relative to newly synthesized molecules. As a class, they have at least tolerable safety and pharmacokinetic profiles, or they would not have been approved in the first place; minimally, one knows what one is dealing with (although it must be noted that, for drug rescue programs, one also knows that one is dealing with drug candidates that have, in fact, failed to reach the clinic). There are no hidden issues with respect to manufacturing or stability issues, and indeed, many drugs are off patent and may provide relatively inexpensive solutions for new problems. And they are available. Pragmatically, one can dovetail a repurposing effort with screening by the modest expedient of replacing a traditional screening library, which often contains hundreds of thousands of compounds, with a much smaller library of approved drug candidates. Such a library is a key component of one important approach to drug repurposing/rescue being carried out under the banner of the newly formed National Center for Advancing Translational Science.⁶⁻⁹ Careful combinatorialization of the screening effort might uncover novel combinations of agents that are superior to single compounds, an approach that would be harder to apply to larger numbers of relatively unknown compound streams that would still require optimization (as might the repurposed drugs as well, but more about that shortly).Other, nonscience-based factors have been partly responsible for the uptick in drug repurposing efforts, especially in academic- or foundation-based drug discovery efforts, many of which do not have at their beck and call a team of highly skilled medicinal chemists. For universities and research institutes seeking to establish themselves as bona fide players in drug discovery, a significant milestone is entry of a compound into clinical trials. The attractiveness of the repurposing approach for that milestone is obvious, even if the validity of entry into clinical trials as the primary measure of success (as opposed to successful passage through clinical trials into the clinic) is subject for discussion. Moreover, when confronted with the recognized difficulties and crushing expense of bringing a molecule all the way from discovery/design/optimization and into the clinic, the allure of a repurposing approach is understandable.What does all of this say about the role of the medicinal chemist in the twenty-first century? Some are quick to point out the downsides of repurposing, ranging from the lack of understanding of how the molecules are working (i.e., when the repurposed drug arose from a phenotypic or alternative assay lacking resolution vis-à-vis target) to the challenges of formulating a workable business model for patenting and employing a treatment that someone already owns. However, to defend traditional drug discovery by pointing to these concerns would be a cop-out. If real cures are to be found through drug repurposing of any ilk, creative solutions to its problems will not be far behind. And we owe it to patients to provide help regardless from which scientific approach the help arises or who benefits. (Remember that stuff about “identifying the best drug regardless of provenance”? I meant it.)It is always dangerous to make predictions and doubly so to do it in print, but here goes. I suspect that drug repurposing, from a strictly scientific perspective, will grow in popularity as its potential is demonstrated and successes are seen. But like combinatorial chemistry and nearly every other “new” technology or approach, it is likely to reach a point where limits become more and more clear. At this point, discovery tools tend to reach their appropriate equilibrium and become accepted, warts and all, for what they are. Unless, in the process, it becomes clear that every useful drug molecule has indeed already been discovered (which is so unlikely, given the vastness of chemical space and the diversity of both target- and nontarget-based challenges in negotiating the biological milieu), de novo and repurposing approaches to drug therapy discovery will coexist.While giving drug repurposing its chance to succeed or fail on its own merits, I’d like to advocate for maintaining a strong pipeline of drugs discovered and developed through de novo medicinal chemistry. This is due to the unique ability of synthetic medicinal chemistry to provide and optimize novel chemical matter and my strong sense that the need for such compounds is not going to end anytime soon. Drug repurposing’s or, especially, drug rescue’s reliance on finding a molecule in just the right chemical spot to cross the goal line is analogous to scoring in American football via pass interception or fumble recovery near the goal line. It is great when it happens, but successful football teams need a diversified strategy that also includes the long game, as tough as it can be. To this point, a case can be made that the additional time needed to optimize a given agent through SAR may not be the overwhelming cost driver in current drug development when compared to the cost of clinical studies.Moreover, far from feeling threatened by drug purposing as a competing strategy, the medicinal chemist should use this tool when it makes sense to do so. Two limiting conditions can be envisioned for a successful repurposing project. In one, the drug acts at the same single target but with different outcomes that depend on the physical site of biological action. Even if the same drug were to be useful in both contexts, one can easily envision different distribution or metabolism issues that would require additional structural tweaking of the compound. Taking advantage of such a situation does require that the medicinal chemist come ready to ply her or his trade in the service of manipulating pharmaceutic properties—which I would argue ought to be part of every discovery scientist’s personal toolbox in any circumstance.The opposite end of the spectrum leads to even more clear-cut conclusions. If the “old” purpose of the drug and the “new” one have different biochemical targets, it is extremely unlikely that the repurposed drug has been preoptimized for the latter situation. In other words, there is no reason to suppose that a structure–activity relationship campaign carried out to optimize a compound for target A would be identical to that needed for compound B. This leads to the familiar situation, described above, where the repurposed drug, even if first-in-class to the clinic, represents a tentative solution that would eventually be rendered obsolete by a subsequent drug that would be even better. Medicinal chemists should feel enabled to tackle such a “fast follow-on” approach to new chemical matter, but to do so, they will have to come to grips with the understanding that the best way forward may not allow them to have the satisfaction of having invented the whole scaffold from the project’s inception (IP attorneys will have to deal with the business and legal aspects of the same realization as well). Some solace may be taken from the fact that, if the repurposed drug is a member of a privileged class of chemical matter, many of the synthetic analogues needed may well already exist in the physical universe and be available at relatively modest expense.As long as the field has existed, medicinal chemistry has sought to incorporate new tools and approaches to accomplish its mission of providing society with new and better drugs. Drug resourcing need not deter us from this path, even if it means that the mission statement will sometimes be edited to read “providing society with better drugs that are not necessarily so new”. So long as the field of medicinal chemistry continues to demonstrate its worth by providing novel solutions to important problems, and so long as these efforts are supported by the business and academic research communities, we will earn our place in the global biomedical research community.     

Molecular modeling and computer aided drug design. Examples of their applications in medicinal chemistry

The development of new drugs with potential therapeutic applications is one of the most complex and difficult process in the pharmaceutical industry. Millions of dollars and man-hours are devoted to the discovery of new therapeutical agents. As, the activity of a drug is the result of a multitude of factors such as bioavailability, toxicity and metabolism, rational drug design has been utopias for centuries. Very recently, impressive technological advances in areas such as structural characterization of biomacromolecules, computer sciences and molecular biology have made rational drug design feasible. The aim of this review is to give an outline of studies in the field of medicinal chemistry in which molecular modeling has helped in the discovery process of new drugs. The emphasis will be on lead generation and optimization.     

Discontinued drugs 2007: central and peripheral nervous system drugs

The development of novel drugs falls into two completely different categories: truly novel drugs and drugs that can be considered as improvements of further advanced and eventually marketed drugs. The risk of failure and the reason for failure by these two classes of compounds obviously are very different. Truly novel drugs often rely on pharmacological data obtained in preclinical models paired with a scientific rationale for a mechanism thought to be relevant for the phenotype of the disease. The scientific insight into both the mechanisms underlying the disease and how these diseases can be manipulated by pharmacological means is therefore essential for the success of the drug. In practical terms, this means that a thorough understanding of the disease is a prerequisite for success. It is therefore a sobering thought that most of these compounds fail due to marginal efficacy in Phase II or III trials. The lack of success of these compounds may reflect either lack of knowledge of the disease, poor predictive value of the preclinical models, large heterogeneity in the underlying mechanisms for a given phenotype, or the use of the compound in a population that doesn't express a phenotype optimal for the drug. This year's list of discontinued compounds spans the range from truly innovative drugs to ‘me-too’ compounds and as such is highly useful in illustrating the current dilemmas for the pharmaceutical industry.     

Multifunctional ligands in medicinal inorganic chemistry--current trends and future directions

This review will highlight recent advances in ligand design for innovative applications in medicinal inorganic chemistry. Ligands that effectively bind metal ions and also include specific features to enhance targeting, reporting, and overall efficacy are driving innovation in areas of disease diagnosis and therapy. Increasing the potency of therapeutic compounds, while limiting side-effects, is a common goal in medicinal chemistry. In an effort to achieve this goal, compounds are being developed that either target a disease site, or are activated by a disease specific biological process. Metal complexes containing targeting functions and/or bioactive ligands, as well as agents that are activated by specific enzymes, or changes in pH and pO2, provide new avenues for drug development. Radiodiagnostic compounds, magnetic resonance imaging agents, and optical probes containing transition metals offer versatility unavailable to organic imaging agents. In certain cases, dual modality agents have been developed, and will be highlighted. Finally, we will discuss targeted metal binding compounds for treatment of metal overload disorders, and the recent application to neurodegenerative disease.     

Plant pharmacophylogeny: past,present and future

The concept of "pharmacophylogeny" was proposed by Peigen Xiao in the 1980s based on long-term studies of Chinese researchers since ancient times and especially the 1950s. The complicated relationships and connectivity between kinship of medicinal plants, their chemical profiles and therapeutic utilities are consistent goals of pharmacophylogeny studies, which benefit innovative drug R&D. In the present work, we reviewed the origin and a brief history of research in this field, as well as the status quo and recent progress of pharmacophylogeny. The concept "pharmacophylogenomics" is put forward to represent the expanding utility of pharmacophylogeny in botanical drug R&D. Pharmacophylogeny and pharmacophylogenomics are the synthesis of multiple disciplines, such as chemotaxonomy, plant morphology, plant biochemistry/molecular biology and omics, etc. Medicinal plants within the same phylogenetic groups may have the same or similar therapeutic compounds/effects, thus forming the core of pharmacophylogeny, which is the scientific law summed up from practice and applied to practice after refining and sublimation. In the past, pharmacophylogeny plays a big role in looking for alternative resources of imported drugs in China. At present, it continues to play an active role in expanding medicinal plant resources, quality control/identification of herbal medicines, as well as predicting the chemical constituents or active ingredients of herbal medicine and the identification and determination of chemical constituents. In the ongoing future, it will play a bigger role in the search for new drugs, sorting out, summarizing, and improving herbal medicine experiences, thus boosting the sustainable conservation and utilization of traditional/natural?medicinal resources.     

2002-2004年上海市药品申报注册情况分析与评价

目的:总结上海市药品申报注册情况,为本市新药的研发提供依据。方法:对2002—2004年上海市药品申报注册的数据进行统计分析和评价,并与全国的情况作了比较。结果:上海市新药申报数量比较稳定,质量较高,但新药本地产业化比例不高;仿制药品逐年增加。结论:应进一步加强创新药物的研发力度,提高本市新药的申报数量和本地产业化率。     

Dendrimer based anti-infective and anti-inflammatory drugs

Alternatives to traditional antibiotics and to antiviral and anti-inflammatory drugs are much in need and the molecular design and development of anti-infective compounds constitute a pivotal area in modern medicinal research. Dendrimers are a relatively new class of structurally well-defined, i.e. monodisperse, synthetic polymers with hyperbranched structures which enable a given molecular motif to be presented in a highly multivalent fashion. Several types of dendrimers with various structural elements and molecular dimensions are commercially available at an affordable price. The surface of dendrimers can be modified relatively easily and, depending on the surface motif, the pharmacological properties of the dendrimer such as cytotoxicity, bacteriocidal and virucidal effect, biodistribution and biopermeability may be modulated to fit a specific medicinal purpose. Dendrimers are thus highly suitable tools in drug discovery and they allow the synthesis of molecules with high and specific binding affinities to a wide variety of receptors, viruses and bacteria. Hence the use of dendrimers for the development of antiviral or antibacterial drugs, destroying the infective agent or disrupting multivalent binding interactions between the infective agent and cells of the host organism has become a highly active research field. The wide range of applications reported for the use of dendrimers as anti-infective and anti-inflammatory drugs in the patent literature demonstrates the general applicability of these molecules as drug candidates. The present review will briefly treat the intrinsic properties of dendrimers in biological systems, as well as general concerns regarding the treatment of infective diseases. The use of dendrimers as anti-infective and anti-inflammatory drugs will be based on a thorough review of the recent patent literature.     

Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells III. Lethal action to man of 43 drugs related to the HeLa cell toxicity of the lethal drug concentrations

The human lethal plasma concentrations of 46 drugs were divided by their IC50 for HeLa cells in vitro to make up a series of cytotoxic quotients (CQL_v). CQL_v was then compared with the recorded lethal action to man of 43 of the drugs. While the 7 drugs with the lowest CQL_v values produce a non-cytotoxic interference with neuro-transmission, most of the remaining 36 drugs have a known local or systemic cytotoxicity to man. A majority of the 36 drugs induces a non-specific central nervous system (CNS)-depression at lethal dosage, intermingled with function loss from organs outside CNS in proportion to decreasing drug accumulation in CNS cells and increasing CQL_v. The remaining drugs which do not penetrate CNS cells and at lethal dosage induce a widespread injury and function loss of tissues outside the CNS, have a CQL_v near unity. Non-specific CNS-depression may thus be the primary human reaction to lethal systemic drug cytotoxicity, while wide-spread drug injury to various tissues outside CNS — conventionally considered to be cytotoxic in origin — may be the obligatory human reaction to drugs that do not penetrate cells well. The present findings indicate a relevance to human toxicity of the HeLa toxicity for most drugs.     

Medicamentos biosimilares. Controversias científicas y legales

Patent expiry dates for early biotechnological drugs is giving rise to the availability of biosimilar drugs. According to the EMEA, these are defined as drugs with a biotechnological origin that have proven comparable to their reference product once the latter's patent expired. Modifications in the manufacturing process of biotechnological medications or treatment changes from one biotechnological molecule to another have not been debated until these biosimilar drugs have become available. It is then that, among other issues, the potential risks of their substitution for reference molecules became controversial. EMEA guidelines for biosimilar drug approval grant that these will be as effective and safe as any other newly available biotechnological medicinal product, or as any other drug undergoing changes in its manufacturing processes once marketed. Their availability will promote competition and reduce the high financial impact healthcare systems endure following the introduction of new therapies based on biotechnological drugs.     

Strategies in the rational drug design

Rational design is applied in the discovery of novel lead drugs. Its rapid development is mainly attributed to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few decades. The promising feature that characterizes the application of rational drug design is that it uses for developing potential leads in drug discovery all known theoretical and experimental knowledge of the system under study. The utilization of the knowledge of the molecular basis of the system ultimately aims to reduce human power cost, time saving and laboratory expenses in the drug discovery. In this review paper various strategies applied for systems which include: (i) absence of knowledge of the receptor active site; (ii) the knowledge of a homology model of a receptor, (iii) the knowledge of the experimentally determined (i.e. X-ray crystallography, NMR spectroscopy) coordinates of the active site of the protein in absence and (iv) the presence of the ligand will be analyzed.