Drug metabolism and pharmacokinetics in drug discovery

The discovery and development of new drugs seems to be an inefficient process, since too few new chemical entities (NCEs) successfully make it to the market. Because one of the main reasons for failure in development is thought to be poor pharmacokinetics (PK), drug metabolism and PK (DMPK) have assumed a central role within the field of drug discovery. A good development candidate requires a balance of potency, safety and PK; therefore, techniques that can help understand these characteristics are employed to enable researchers to design more robust candidates. A number of new in silico, in vitro and in vivo techniques are available to screen compounds for key absorption, distribution, metabolism and excretion (ADME) characteristics, which, when applied within a rational strategy, can make a major contribution to the design and selection of successful NCEs.     

New horizons in drug metabolism,pharmacokinetics and drug discovery

Along with minimal toxicity, good drug metabolism and pharmacokinetic (DMPK) properties are essential for the clinical success of a drug candidate. A major cause of failure of orally administered drugs during their development is the discovery that in humans they have low intestinal absorption and/or high clearance causing low and variable bioavailability. In addition, drug interactions and the presence of active metabolites can prevent or complicate their successful development. With poor pharmacokinetics it can be difficult to achieve a suitable dosage regimen for the required pharmacodynamic action. The main role of DMPK in discovery is, therefore, the prediction of human pharmacokinetics and metabolism. Reducing the rate of attrition during drug discovery and development is now considered essential, particularly as it is now possible to screen an ever-greater number of compounds.     

Toward in silico structure-based ADMET prediction in drug discovery

Quantitative structure-activity relationship (QSAR) methods and related approaches have been used to investigate the molecular features that influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. As the three-dimensional structures of several major ADMET proteins become available, structure-based (docking-scoring) computations can be carried out to complement or to go beyond QSAR studies. Applying docking-scoring methods to ADMET proteins is a challenging process because they usually have a large and flexible binding cavity; however, promising results relating to metabolizing enzymes have been reported. After reviewing current trends in the field we applied structure-based methods in the context of receptor flexibility in a case study involving the phase II metabolizing sulfotransferases. Overall, the explored concepts and results suggested that structure-based ADMET profiling will probably join the mainstream during the coming years.     

The pivotal role of drug metabolism and pharmacokinetics in the discovery and development of new medicines

An appropriate drug metabolism and pharmacokinetic (DMPK) profile remains a major hurdle to reducing risk and improving productivity in pharmaceutical R&D, accounting for approximately 40% of all drug failures. For orally administered drugs, failure is often attributable to low intestinal absorption and/or high clearance, causing poor and variable bioavailability. Additional reasons for failure include drug-drug interactions and the presence of active metabolites. With a poor pharmacokinetic profile, it can be difficult to achieve the dose profile required for therapeutic efficacy. The main role that DMPK plays in drug discovery is therefore the prediction of drug metabolism and pharmacokinetics in humans. Successful prediction can be expected to reduce the rate of attrition during drug discovery and development. This has led to the recognition that DMPK is an essential component of the drug discovery process. Both this and the need to screen ever greater numbers of compounds have led to major changes in both technology and the process of drug discovery.     

Cytomics as a new potential for drug discovery

At the single-cell level in conjunction with data-pattern analysis, high-content screening by image analysis or flow cytometry of clinical cell- or tissue-section samples provides differential molecular profiles for the personalized prediction of therapy-dependent disease progression in patients. The molecular reverse-engineering of these molecular profiles, which is the exploration of molecular pathways, backwards, to the origin of the observed molecular differentials, by systems biology has the potential to detect new drug targets in knowledge spaces, typically inaccessible to traditional hypotheses. Furthermore, predictive medicine, by cytomics in stratified patient groups, opens a new way for personalized (or individualized) medicine, as well as for the early detection of adverse drug reactions in patients.     

Approaches to higher-throughput pharmacokinetics (HTPK) in drug discovery

With pressure on pharmaceutical companies to reduce time-to-market and improve the success rate of new drug candidates, higher-throughput pharmacokinetic (HTPK) support has become an integral part of many drug discovery programmes. This report details the amalgamation of robotics, new sample preparation technologies and highly sensitive and selective mass spectrometric detection systems to deliver the promise of HTPK. A historical perspective on automated bioanalysis with the current approaches and future prospects for the discipline are described.     

Physiologically-based modeling of monoclonal antibody pharmacokinetics in drug discovery and development

Over the past few decades, monoclonal antibodies (mAbs) have become one of the most important and fastest growing classes of therapeutic molecules, with applications in a wide variety of disease areas. As such, understanding of the determinants of mAb pharmacokinetic (PK) processes (absorption, distribution, metabolism, and elimination) is crucial in developing safe and efficacious therapeutics. In the present review, we discuss the use of physiologically-based pharmacokinetic (PBPK) models as an approach to characterize the in vivo behavior of mAbs, in the context of the key PK processes that should be considered in these models. Additionally, we discuss current and potential future applications of PBPK in the drug discovery and development timeline for mAbs, spanning from identification of potential target molecules to prediction of potential drug-drug interactions. Finally, we conclude with a discussion of currently available PBPK models for mAbs that could be implemented in the drug development process.     

Microwave-assisted high-speed chemistry: a new technique in drug discovery

In both lead identification and lead optimization processes there is an acute need for new organic small molecules. Traditional methods of organic synthesis are orders of magnitude too slow to satisfy the demand for these compounds. The fields of combinatorial and automated medicinal chemistry have been developed to meet the increasing requirement of new compounds for drug discovery; within these fields, speed is of the essence. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry. We believe that the time saved by using focused microwaves is potentially important in traditional organic synthesis but could be of even greater importance in high-speed combinatorial and medicinal chemistry.     

DNA demethylases: a new epigenetic frontier in drug discovery

DNA methylation is one of the most extensively studied, and one of the most stable, of all epigenetic modifications. Two drugs that target DNA methyltransferase enzymes are licensed for clinical use in oncology but relatively little attention has focused on the enzymatic pathways by which DNA methylation can be reversed. Recent breakthroughs have identified at least two classes of enzymes that can achieve functional reversal. This review discusses the significance of DNA demethylation in a range of human diseases, the candidate proteins that mediate the demethylation and the opportunities and challenges in targeting these candidates to develop new therapeutics.     

The development of label-free cellular assays for drug discovery

Introduction: The need to improve drug research and development productivity continues to drive innovation in pharmacological assays. Technologies that can leverage the advantages of both molecular and phenotypic assays would hold great promise for discovery of new medicines. Areas covered: This article briefly reviews current label-free platforms for cell-based assays and is primarily focused on fundamental aspects of these assays using dynamic mass redistribution technology as an example. The article also presents strategies for relating label-free profiles to molecular modes of actions of drugs. Expert opinion: Emerging evidence suggests that label-free cellular assays are phenotypic in nature, yet permit molecular mechanistic deconvolution. Together with unique competency in throughput, sensitivity and pathway coverages, label-free cellular assays allow users to screen drugs against endogenous receptors in native cells (including disease relevant primary cells) and determine the molecular modes of action of drug molecules. However, there are challenges for label-free in both basic research and drug discovery: the deconvolution of the cellular and molecular mechanisms for the biosensor signatures of receptor-drug interactions, new methodologies for data analysis and the development of new biosensor technologies. These challenges will need to be met for the wide adoption of these assays in drug discovery.     

The development of label-free cellular assays for drug discovery

Introduction: The need to improve drug research and development productivity continues to drive innovation in pharmacological assays. Technologies that can leverage the advantages of both molecular and phenotypic assays would hold great promise for discovery of new medicines.

Areas covered: This article briefly reviews current label-free platforms for cell-based assays and is primarily focused on fundamental aspects of these assays using dynamic mass redistribution technology as an example. The article also presents strategies for relating label-free profiles to molecular modes of actions of drugs.

Expert opinion: Emerging evidence suggests that label-free cellular assays are phenotypic in nature, yet permit molecular mechanistic deconvolution. Together with unique competency in throughput, sensitivity and pathway coverages, label-free cellular assays allow users to screen drugs against endogenous receptors in native cells (including disease relevant primary cells) and determine the molecular modes of action of drug molecules. However, there are challenges for label-free in both basic research and drug discovery: the deconvolution of the cellular and molecular mechanisms for the biosensor signatures of receptor–drug interactions, new methodologies for data analysis and the development of new biosensor technologies. These challenges will need to be met for the wide adoption of these assays in drug discovery.     

Aging biology: a new frontier for drug discovery

Introduction: The prevalence of age-related pathologies, such as cardiovascular disease, neurodegenerative disease and diabetes type II, has increased dramatically with the rising average age of populations. Antiaging molecules and appropriate animal models need to be developed to prevent and or delay alterations that occur during aging and are manifested as age-associated illnesses.

Areas covered: This review covers the main experimental models used in aging research, from invertebrates up to nonhuman primates. The authors discuss studies of the biochemical pathways involved in dietary restriction, which has been associated with life span extension. The authors also describe the implications of sirtuin 1, insulin growth factor, mTOR (the mammalian target of rapamycin) and AMPK activation, which are well-characterized antiaging pathways. All these pathways are highly conserved from invertebrates to nonhuman primates. Although some invertebrate models are used to study the antiaging properties of drugs, mice models and nonhuman primates are more suitable, as the study of changes in memory loss is critical. The review highlights the conservation of the aging pathways between species.

Expert opinion: Further studies on aging should focus on two ways: i) improving animal models, for example, the genetically heterogeneous mice and ii) drug research. It is almost impossible to evaluate clinically the efficacy of antiaging drugs. Moreover, caloric restriction currently constitutes the most effective antiaging pathway. Thus, the strategy is to study drugs for aging-associated diseases, such as diabetes, that also have antiaging effects.     

Aging biology: a new frontier for drug discovery

INTRODUCTION: The prevalence of age-related pathologies, such as cardiovascular disease, neurodegenerative disease and diabetes type II, has increased dramatically with the rising average age of populations. Antiaging molecules and appropriate animal models need to be developed to prevent and or delay alterations that occur during aging and are manifested as age-associated illnesses. AREAS COVERED: This review covers the main experimental models used in aging research, from invertebrates up to nonhuman primates. The authors discuss studies of the biochemical pathways involved in dietary restriction, which has been associated with life span extension. The authors also describe the implications of sirtuin 1, insulin growth factor, mTOR (the mammalian target of rapamycin) and AMPK activation, which are well-characterized antiaging pathways. All these pathways are highly conserved from invertebrates to nonhuman primates. Although some invertebrate models are used to study the antiaging properties of drugs, mice models and nonhuman primates are more suitable, as the study of changes in memory loss is critical. The review highlights the conservation of the aging pathways between species. EXPERT OPINION: Further studies on aging should focus on two ways: i) improving animal models, for example, the genetically heterogeneous mice and ii) drug research. It is almost impossible to evaluate clinically the efficacy of antiaging drugs. Moreover, caloric restriction currently constitutes the most effective antiaging pathway. Thus, the strategy is to study drugs for aging-associated diseases, such as diabetes, that also have antiaging effects.     

多靶点药物治疗及药物发现

作用于单靶点的药物在治疗复杂性疾病如肿瘤、糖尿病、感染性疾病时常常疗效不佳或毒性较大。多靶点药物可以同时调节疾病网络系统中的多个环节,不易产生抗药性,对各靶点的作用产生协同效应,达到最佳的治疗效果。本文对多靶点药物治疗的特点、分类情况、发现策略、筛选模型及已在临床使用的多靶点治疗药物进行综述,并探讨中药在多靶点药物治疗应用中的潜力。     

药代动力学人体预测及其在新药研发中的应用

药物代谢和药代动力学(DMPK)通过揭示药物的体内代谢处置过程,理解药物药理效应和毒副反应的体内物质基础,是连接药物分子及其性质与生物学效应的桥梁。DMPK人体预测应用模型拟合技术,由人体外试验数据和动物体内外数据预测人体药代动力学性质,并与药效动力学和毒性评价相关联,可提高新药研发效率、降低临床失败率和节省资源。经典的异速放大法和体外-体内外推法主要用于预测人体清除率和稳态表观分布容积等重要的药代动力学参数。近10年来,基于生理的药代动力学模型(PBPK)的快速发展和应用实践,推动了DMPK人体预测在新药研发、药物监管、临床合理和个体化用药中的应用。PBPK模型不仅能预测消除和分布等参数,还能用于药物人体药代动力学行为的预测,包括血药浓度-时间曲线和药物-药物相互作用,以及不同人群体内药代动力学和药代-药效预测。作为新药研发的转化科学技术以及个体化用药的指导工具,DMPK人体预测将具有更为广泛的应用价值。     

Novel anticancer targets and drug discovery in post genomic age

Cancer is a serious disease with a complex pathogenesis, which threats human life greatly. Currently, great efforts have been put to the identification of novel anticancer targets and the discovery of anticancer drugs following the progress of chemogenomics, which will be reviewed briefly in this article. Furthermore, during the past 5 years, the global effort of sequencing human genome has provided us with an enormous number of potential targets associated with cancer therapy. As a result, the New Drug Discovery (NDD) is undergoing a transition "from gene to drug". Accordingly, the targets for anticancer drugs studies now are focused on some biological macromolecular targets associated with cancer and several interactive mechanisms involved in the growth and metastasis of cancer cells as well as tumor angiogenesis, such as Matrix Metalloproteinases (MMPs), Aminopeptidase N (APN), Tyrosine Kinase (TK), Farnesyltransferase (FTase) and cell Signal Transduction Pathway and so forth. Among these targets the MMP-2, -9 and APN are the most extensively studied enzymes in our laboratory. The peptidomimetics Matrix Metalloproteinase Inhibitors (MMPIs) and APN inhibitors (APNIs) with the molecular scaffold of pyrrolidine, 3-amino-2-hydroxy-4-phenyl butyric acid (AHPA) and glutamylide, which have been designed and synthesized in our laboratory, will be described in the review, among which the pyrrolidine scaffold is patented with the IC(50) ranging from 1 nM to 300 nM against MMP-2, and MMP-9.