Drug Discovery Process - PHSC 3107 Unit 2.1 PDF

Module 2: Drug Discovery The Drug Discovery Process Gerard Lee L. See, RPh, PhD Florencio V. Arce, Jr., RPh, PhD...

Module 2: Drug Discovery The Drug Discovery Process Gerard Lee L. See, RPh, PhD Florencio V. Arce, Jr., RPh, PhD Beatrix B. Loyao, RPh, MSc DEPARTMENT OF PHARMACY 1 SCIENTIA VIRTUS DEVOTIO  Drug discovery process ▶ The creation of a new drug can be broadly divided into three main phases: - Drug discovery – from therapeutic concept to molecule - Drug development – from molecule to registered product - Commercialization – from product to therapeutic application to sales. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 2  Drug discovery process ▶ The three components of the overall process are not independent and consecutive stages, but have to be closely coordinated at all stages of the project. At the outset of any new project, the criteria against which the plan will be judged include not only its scientific strength and originality but, importantly, development and marketing issues. ▶ Previously, the process was much more compartmentalized: scientists produced molecules, development functions were responsible for checking their safety and turning them into registrable drugs, and the marketing department generated sales and turned them into revenues. The drop-out rate was not excessive, because regulatory requirements were less stringent, and the failures were not expensive. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 3  Drug discovery process ▶ Since then, biomedical science has advanced dramatically, drug discovery and development have become more technology-driven and, hence, expensive, regulatory requirements are much more stringent, and the competition is more intense. ▶ An additional complication is that of the increased amount of work being done in partnership with other companies or with academic groups, adding the need for alliance as well as project management. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 4 Drug discovery process Drug discovery phase of a typical project aimed at producing a new synthetic drug SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 5 Drug Discovery Process SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 6  Drug discovery process ▶ Drug discovery phase starts with the choice of a disease area and defining the therapeutic need that is to be met. It proceeds to the identification of the biochemical, cellular or pathophysiological mechanism target, and, if possible, the identification and validation of a molecular ‘drug target’. Next comes the identification of a lead structure, followed by the design, testing and fine-tuning of the drug molecule to the point where it is deemed suitable for development. ▶ The strong emphasis on defined molecular (normally protein) drug targets as a starting point is too recent. In the ‘premolecular’ drug discovery era, targets were mainly pathophysiological or biochemical mechanisms, such as blood pressure regulation, inflammation or cholesterol metabolism, of which the molecular components were not yet defined. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 7  Drug discovery process ▶ Until about 1980 the use of molecular targets were rarely feasible; even when the ‘target’ was defined, for example as an enzyme or a receptor, it was seldom available in sufficient quantities in a purified functional form to be used as the basis for screening assays. Instead, the functional activity of the target was measured by indirect means in isolated tissue preparations, or even in whole animals, methods which we nowadays regard as too slow, laborious and error prone to place at the front end of a drug discovery project. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 8  Drug discovery process ▶ Biopharmaceutical agents are very diverse, including endogenous mediators, monoclonal antibodies and vaccines, and in the future, no doubt, products for siRNA and gene therapy applications. ▶ Where endogenous molecules are involved, the concept of targets and lead compounds has much less relevance, as nature has done the discovery part of the work, so once the therapeutic relevance of the substance has been established, the problems mainly revolve around the production, purification and formulation of the material in a form suitable for the market. With other kinds of biopharmaceuticals, such as therapeutic antibodies, the molecular target will generally be chosen in advance, and the main task is to obtain an antibody with the required properties. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 9  Drug discovery process ▶ A glance at the pharmacopoeia will show that many therapeutic agents, particularly anti-infective and anti- tumour drugs, originate from natural products, rather than synthetic molecules. ▶ Exploiting such a ready-made compound library is seen as an attractive strategy which has led to some important therapeutic breakthroughs, such as the anti-malarial drug artemisinin, immunosuppressants such as ciclosporin, fujimycin (FK506) and rapamycin, as well as paclitaxel and other recently introduced anticancer drugs such as epothilones. ▶ Access to source material in remote places, prevailing political conditions, and the continuing availability of the active compound can be troublesome. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 10 Case histories SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 11 Case histories Discovery pathways of some successful projects SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 12  Case histories ▶ One common feature that emerges from a survey of the many anecdotal reports of drug discovery projects is that they often have outcomes quite different from what was originally intended. ▶ Increasing the emphasis on defined molecular targets as starting points for drug discovery projects would reduce the likelihood of such therapeutic surprises. ▶ Lack of efficacy in clinical trials is a measure of our inability to predict therapeutic efficacy on the basis of pharmacological properties – remains one of the commonest causes of project failure, accounting for 30% of failures, second only to pharmacokinetic shortcomings (39%). SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 13 Stages of drug discovery SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 14  Stages of drug discovery ▶ A huge number of ‘theoretical’ compounds (far too many to be physically accessible) is first ‘filtered’ in silico to reduce it to a practicable number of compounds that is available, or can be synthesized, in screening libraries. ▶ High-throughput screening is then used to identify ‘hits’, which show significant activity in the chosen screen. This may throw up hundreds or thousands of compounds, depending on the nature of the screen and the size and quality of the library. ▶ ‘Validation’ of ‘hits’ entail assessment of the structure–activity relationships within the screening library, and whether the hit belongs to a family of compounds – a ‘hit series’ – which represents a reasonable starting point for further chemistry. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 15  Stages of drug discovery ▶ In lead identification, the validated hits are subjected to further scrutiny, particularly in respect of their pharmacokinetic properties and toxicity as well as addressing in more detail the feasibility of building a synthetic chemistry program. In this process, the handful of ‘hit series’ is further reduced to one or a few ‘lead series’. ▶ Synthetic chemistry then begins, in the ‘lead optimization’ stage. This usually involves parallel synthesis to generate derivatives of the lead series, which are screened and profiled with respect to pharmacology, pharmacokinetics and toxicology, to home in on a small number of ‘drug candidates’ judged suitable for further development, at which point they are taken into preclinical development. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 16  Trends in drug discovery ▶ Drug discovery has become focused on cloned molecular targets that can be incorporated into high- throughput screens. Target selection now assumes a significance that it rarely had in the past which began without any molecular target in mind, which would seldom be the case nowadays. ▶ The interval from from the start of the project to identification of the compound has now been substantially reduced (3 years or less) once a molecular target has been selected, mainly as a result of (a) high-throughput screening of large compound libraries (including natural product libraries) to identify initial lead compounds; (b) improvements at the lead optimization stage whereby the results of compound screening are analyzed to reveal the molecular configurations that are associated with biological activity. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 17  Trends in drug discovery ▶ The main reasons that compounds fail, apart from lack of efficacy or unexpected side effects, are that they show toxicity, or that they have undesirable pharmacokinetic properties (e.g. poor absorption, too long or too short plasma half-life, unpredictable metabolism, accumulation in tissues, etc.). ▶ In the past, these aspects of a drug’s properties were often not investigated until the discovery/development hurdle had been crossed, as investigating them was traditionally regarded as a responsibility of ‘development’ rather than ‘research’. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 18  Trends in drug discovery ▶ Frequently a compound would fail after several months in preclinical development – too late for the problem to be addressed by the drug discovery team, which had by then moved on. This highlighted the need to incorporate pharmacokinetic and toxicological studies, as well as pharmacological ones, at an earlier stage of the project, during the lead optimization phase. ▶ Inevitably this has a cost in terms of time and money, but this will be more than justified by a reduction in the likelihood of compounds failing during clinical development. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 19 SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 20 20 SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 21 21  Trends in drug discovery ▶ A massive expansion of the compound collections used as starting points, from large ‘white-powder’ libraries of 100000 or more compounds created during the 1990s, to massive virtual libraries of tens of millions. ▶ Use of automated synthesis methods to accelerate lead optimization. ▶ To deal with large, compound libraries, the introduction of high-throughput screens for actual compounds, and in silico screens for virtual compounds. ▶ Increasing reliance on in silico predictions to generate leads. ▶ Focus on cloned human targets as starting points. ▶ Progressive ‘front-loading’ of assessment of drug metabolism and pharmacokinetic characteristics, including in silico assessment of virtual libraries. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 22  Project planning ▶ When a project moves from the phase of exploratory research to being an approved drug discovery project to which specific resources are assigned under the direction of a project leader, its objectives, expected timelines and resource requirements need to be agreed by the members of the project team and approved by research management. ▶ The early drug discovery phase of the project will typically begin when a target has been selected and the necessary screening methods established, and its aim will be to identify one or a few ‘drug candidates’ suitable for progressing to the next stage of preclinical development. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 23 SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 24 24  Project planning ▶ Where appropriate (e.g., potency, oral bioavailability), quantitative limits will normally be set. Such a list of necessary or desirable features, based on results from many independent assessments and experimental tests, provides an essential focus for the project. ▶ There are, in essence, two balancing components of a typical project: - Designing and synthesizing novel compounds. - Filtering, to eliminate compounds that fail to satisfy the criteria. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 25  Project planning ▶ An important aspect of project planning is deciding what tests to do when, so as to achieve the objectives as quickly and efficiently as possible. ▶ The factors that have to be taken into account for each test are: - Compound throughput - Cost per compound - Amount of compound required in relation to amount available - ’Salience’ of result (i.e., is the criterion an absolute requirement, or desirable but non-essential?) - Probability that the compound will fail. SCIENTIA VIRTUS DEVOTIO DEPARTMENT OF PHARMACY 26