CNS drug discovery: challenges and solutions

The worldwide market for therapies for central nervous system (CNS) disorders was valued at around US dollars 50 billion in 2001, and is set to grow sharply in the years ahead. This is because of a marked increase in the number of people aged over 65 (the "baby boomer" effect), which will lead to increased demand for more safe and effective medicines for CNS disorders. This one-day Society for Medicines Research symposium, held September 23, 2004, in London, United Kingdom, was organized by Dr. Alan M. Palmer (Pharmidex, London, U.K.) and Prof. F. Anne Stephenson (School of Pharmacy, University of London, U.K.). More than 100 delegates heard a scholarly and comprehensive review of the challenges currently facing CNS research and development, which was accompanied by consideration of a variety of innovative solution strategies. The meeting considered: 1) how to identify and validate targets for potential CNS drugs; 2) how to assess brain penetration (both in vitro and in vivo); 3) how to develop in silico methodologies to predict blood-brain barrier penetration; 4) how to assess therapeutic efficacy (both in vitro and in vivo); 5) how to establish reliable biomarkers to guide decision making; and 6) how to effectively apply magnetic resonance imaging to CNS drug discovery.     

Receptorome screening for CNS drug discovery

An estimated 50% of currently marketed drugs target G protein-coupled receptors (GPCRs) for a wide variety of indications, including central nervous system (CNS) disorders. Although drug discovery efforts have focused on GPCRs, less than 10% of GPCRs are currently used as drug targets. Thus, GPCRs continue to represent a significant opportunity for future CNS drug development. Identifying the molecular targets of psychoactive compounds may result in the elucidation of novel targets for CNS drug discovery. This commentary will describe discovery-based approaches and provide several recent examples of novel ligand-receptor interactions discovered through systematic screening of the 'receptorome'.     

Structure-based drug discovery and protein targets in the CNS

Structure-based methods are having an increasing role and impact in drug discovery. The crystal structures of an increasing number of therapeutic targets are becoming available. These structures can transform our understanding of how these proteins perform their biological function and often provide insights into the molecular basis of disease. In addition, the structures can help the discovery process. Methods such as virtual screening and experimental fragment screening can provide starting hit compounds for a discovery project. Crystal structures of compounds bound to the protein can direct or guide the medicinal chemistry optimisation to improve drug-like properties - not only providing ideas on how to improve binding affinity or selectivity, but also showing where the compound can be modified in attempting to modulate physico-chemical properties and biological efficacy. The majority of drug discovery projects against globular protein targets now use these methods at some stage.This review provides a summary of the range of structure-based drug discovery methods that are in use and surveys the suitability of the methods for targets currently identified for CNS drugs. Until recently, structure-based discovery was difficult or unknown for these targets. The recent determination of the structures of a number of GPCR proteins, together with the steady increase in structures for other membrane proteins, is opening up the possibility for these structure-based methods to find increased use in drug discovery for CNS diseases and conditions.     

Modeling heart failure in animal models for novel drug discovery and development

Introduction: When investigating drugs that treat heart diseases, it is critical when choosing an animal model for the said model to produce data that is translatable to the human patient population, while keeping in mind the principles of reduction, refinement, and replacement of the animal model in the research.

Areas covered: In this review, the authors focus on mammalian models developed to study the impact of drug treatments on human heart failure. Furthermore, the authors address human patient variability and animal model invariability as well as the considerations that need to be made regarding choice of species. Finally, the authors discuss some of the most common models for the two most prominent human heart failure etiologies; increased load on the heart and myocardial ischemia.

Expert opinion: In the authors’ opinion, the data generated by drug studies is often heavily impacted by the choice of species and the physiologically relevant conditions under which the data are collected. Approaches that use multiple models and are not restricted to small rodents but involve some verification on larger mammals or on human myocardium, are needed to advance drug discovery for the very large patient population that suffers from heart failure.     

Novel CNS drug discovery and development approach: model-based integration to predict neuro-pharmacokinetics and pharmacodynamics

Introduction: CNS drug development has been hampered by inadequate consideration of CNS pharmacokinetic (PK), pharmacodynamics (PD) and disease complexity (reductionist approach). Improvement is required via integrative model-based approaches.

Areas covered: The authors summarize factors that have played a role in the high attrition rate of CNS compounds. Recent advances in CNS research and drug discovery are presented, especially with regard to assessment of relevant neuro-PK parameters. Suggestions for further improvements are also discussed.

Expert opinion: Understanding time- and condition dependent interrelationships between neuro-PK and neuro-PD processes is key to predictions in different conditions. As a first screen, it is suggested to use in silico/in vitro derived molecular properties of candidate compounds and predict concentration-time profiles of compounds in multiple compartments of the human CNS, using time-course based physiology-based (PB) PK models. Then, for selected compounds, one can include in vitro drug-target binding kinetics to predict target occupancy (TO)-time profiles in humans. This will improve neuro-PD prediction. Furthermore, a pharmaco-omics approach is suggested, providing multilevel and paralleled data on systems processes from individuals in a systems-wide manner. Thus, clinical trials will be better informed, using fewer animals, while also, needing fewer individuals and samples per individual for proof of concept in humans.     

Adaptivity in drug discovery and development

The development of novel drugs is becoming increasingly challenging, inefficient, and costly, as acknowledged by all major stakeholders of pharmaceutical products. Adaptive designs have attracted considerable attention in recent years, as they promise an increase in efficiency of the drug development process by making better use of the observed data. The key idea of adaptive designs is to use data accumulating from an ongoing experiment to decide on how to modify certain design aspects and better address the question(s) of interest and/or adjust for incorrect assumptions. When planned carefully and applied in appropriate situations, a number of adaptive designs allow for scientifically sound conclusions: early stopping either for futility or for success, sample size reassessment, treatment selection, etc. Most of the current discussions regarding adaptive designs, focus however, on clinical trial applications in the (late) development phase of a novel drug. The aim of this review is to broaden this perspective and to demonstrate that adaptivity is a fundamentally important concept that can be applied to many different stages of drug discovery and development. We review the major statistical methods available for planning and analyzing adaptive designs and then move through the drug discovery and development process and identify possible opportunities for adaptivity. To illustrate the ideas, we refer to examples and case studies from the literature, where available. A brief discussion about regulatory perspectives, operational aspects, and some potential hurdles is also given. Drug Dev Res 70, 2009. © 2009 Wiley‐Liss, Inc.     

Biomarkers in drug discovery and development

Biomarkers have shown promising utilities at various stages of the pharmaceutical R & D. With the recent technological advancements and the introduction of protein and gene arrays, high performance instrumentation (e.g., high-field nuclear magnetic resonance and high-resolution mass spectrometers), and bioinformatics, decisions on safety and efficacy criteria can be made with a higher degree of confidence. However, there is a scarcity of robust and valid biomarkers to accelerate the drug development process from pre-clinical through all stages of clinical studies. In this article, a brief overview of current definitions, biomarker categories, challenges in biological and analytical validation, along with several clinical examples will be presented.     

Psychiatric drug discovery and development

This new conference on Psychiatric Drug Research was organised by the Strategic Research Institute and was chaired by P McGonigle (Wyeth Research, USA) and D Schoepp (Eli Lilly, USA). The 2-day meeting featured presentations from an international assembly of industrial and academic experts who have significantly contributed to the current body of knowledge in the field of psychotherapeutics. D Weinberger (NIMH, USA) gave an elegant keynote lecture on the application of genomics in psychopharmacology. Other presentations covered the latest technological advances, animal models and mechanistic approaches utilised in drug discovery for neuropsychiatric disorders and reviewed the current status of numerous novel targets resulting from these strategies.     

Pharmacological and functional magnetic resonance imaging techniques in CNS drug discovery

Functional magnetic resonance imaging (fMRI) has transformed cognitive neuroscience over the past 10 – 15 years, allowing clinical researchers unprecedented access to the functioning of the human brain under many different conditions including motor, sensory and cognitive stimulation. During the past 5 years, increasing interest has also focused on mapping pharmacologically induced changes in human brain activity produced following exposure to psychoactive agents such as amphetamine and cocaine, and is now frequently termed pharmacological MRI (phMRI). Unfortunately, preclinical fMRI and phMRI studies have not kept pace with human research, largely due to numerous technical hurdles inherent in small laboratory animal imaging, as well as the high cost of necessary equipment. However, this is now set to change with significant investment being made across academic and industry laboratories, as researchers attempt to tap into the huge potential of this noninvasive and powerful translational tool. This review introduces the principles and fundamental assumptions behind the technologies, details some important applications of fMRI and phMRI within a CNS research environment, and examines the potential future impact of the technology.     

Clinical biomarkers in drug discovery and development

Biomarkers enable the characterization of patient populations and quantitation of the extent to which new drugs reach intended targets, alter proposed pathophysiological mechanisms and achieve clinical outcomes. In genomics, the biomarker challenge is to identify unique molecular signatures in complex biological mixtures that can be unambiguously correlated to biological events in order to validate novel drug targets and predict drug response. Biomarkers can stratify patient populations or quantify drug benefit in primary prevention or disease-modification studies in poorly served areas such as neurodegeneration and cancer. Clinically useful biomarkers are required to inform regulatory and therapeutic decision making regarding candidate drugs and their indications in order to help bring new medicines to the right patients faster than they are today.     

Ion channels in drug discovery and development

An excellent meeting on ion channels in drug discovery and development was organised by the Strategic Research Institute. Recent progress in the molecular and cellular biology of ion channels, their localisation and their physio-pathological roles, was presented by a selected number of academic researchers. The status of development, by pharmaceutical companies, of drugs targeting specific ion channel subtypes (e.g., AMPA receptors, nicotinic receptors, GABA(A) receptors, K(+) channels, transient receptor potential channels) and with different modalities (agonists versus potentiators) was reviewed. More comparative data on the emerging ion channel screening technologies are now available and were shared in a number of presentations. Finally, cardiac ion channel liability, in the context of drug discovery and development, was thoroughly discussed.     

Protein kinases in drug discovery and development

The Protein Kinases in Drug Discovery and Development meeting highlighted protein kinases as validated therapeutic targets in many types of disease, especially cancer. Drugs designed to inhibit protein kinase activity were widely tested in preclinical and clinical evaluation, demonstrating significant efficacy with acceptable toxicity profiles. More than 600 kinases are encoded by the human genome, some of which are already well established as validated targets due to extensive scientific research from both academic institutions and industrial companies. As demonstrated by several speakers during the meeting, different diseases exhibit mutations or over-expression of the same kinase. Therefore, a drug designed to inhibit these specific kinases can potentially be used as a therapeutic agent in the treatment of more then one disease. The major strategy employed by most companies today in drug discovery is using genomic information, together with clinical research, to identify novel potential targets. A drug discovery project is then established around the chosen target kinase, in order to identify, optimize and deliver novel potential drugs to clinical trials.