3 Research, Discovery and Development We saw in Section 1.2 that almost any substance has the potential to find use as a pharmaceutical, but how do we know which ones to use? In the days of the herbalist and apothecaries, knowledge was derived from simple empiricism, substances were used when they had been shown to work, and such valuable information was passed on in oral tradition until documentation became available. However, although at the beginning of the 21st century we have far more knowledge than the first century herbalists had, the process of identifying new drugs is, at least in principle, very similar. The following recent quote from a medicinal chemist † is apposite: 51 “In medicinal chemistry we’re still fundamentally an observational science. (That should have been obvious given how little math any of us need to know). We have broad theories, trends, rules of thumb – but none of it is enough to help us very much, and we’re constantly surprised by our data. That can be enjoyable, if you have the right personality type, but it sure isn’t restful, and a lot of the time it isn’t very profitable, either”. The following section provides a simplified overview of the process involved in developing a new pharmaceutical. In view of the low success rate, the R&D departments of research pharmaceutical companies will not just be investigating one drug but, at any one time, will be looking at many different substances at varying points in the development cycle. A large company may have 100–200 substances going through its development pipeline at any one time. 52 3.1 Pre-clinical Trials Identifying a new drug starts with research into the particular illness or disease of interest. This can be being undertaken within the research laboratories of the pharmaceutical company but may also be being carried out in academia, government research organizations, small “boutique” pharmaceutical companies or any combination of these. Medical research is now so complex that large pharmaceutical companies currently undertake most of their research in combination with partners. In those situations where the research identifies a specific receptor or target within the body which could deliver beneficial effects, the search can begin for a potential drug. The target can be a wide variety of things: a particular cell type, enzyme, gene, pathway or process. It is estimated that more than 500 targets are currently under investigation in the research pharmaceutical companies. Once a target has been selected, the next step is to identify any substances that might have some sort of regulating effect on it. Advances in automated chemical synthesis techniques, such as combinatorial chemistry, have enabled chemical libraries to expand rapidly. Aurora Fine Chemicals, 53 for example, has a compound library containing >18 million substances and a compound library for a pharmaceutical company will now typically contain samples of 1–2 million different substances. The search for a likely candidate drug within these vast chemical libraries has been simplified in the 20th century by the introduction of high-throughput screening techniques (HTS) which use advances in robotics, automation, miniaturisation and data handling. 54 In these techniques automated equipment can be used to apply simple biochemical assays to very large numbers of chemicals in a short period of time: throughput can range from 50 000 to 100 000 samples a day. Developments in ultra-high-throughput screening (UHTS) since 2010 now make assay rates of 1 000 000 samples a day possible. Screening usually takes place in several stages. Initially a simple assay is used to pre-screen a very large number of samples, potentially the complete library, although a more clearly defined sub-set is often used. Subsequently a more complex assay will be used to refine the initial group, which might contain several hundred compounds, down to a more manageable number, usually <10. HTS/UHTS techniques can also now be used to provide initial pharmacokinetic information on absorption, distribution, metabolism and excretion (ADME). Guiguemde and colleagues have provided a useful review of the application of these techniques in the search for candidate drugs to cure or alleviate malari a. 55 The outcome of this activity is the identification of a small number of substances that might lead to a candidate drug and eventually to a useable pharmaceutical. This “ Lead Identification ” is the second major stage of the R&D process, following “Target Selection”, and marks the transition from research into development. Although there is probably a further 10 years of development work needed before a drug could be submitted for marketing authorisation, it is at this point that the drug is likely to be patented. The R&D costs up to this point will have been relatively modest at a few million US$, but beyond this point costs escalate rapidly and the business needs to protect its investment. The next step in the process, “ Lead Optimisation ”, endeavours to reduce the number of potential leads from ca . 10–15 down to 3–4 substances. At the same time, attempts will be made to modify the molecular structure in various ways in the hope of increasing the efficacy whilst simultaneously decreasing any potential side effects. This sounds simple but will usually take 2–3 years of detailed pre-clinical experimentation using in silico , in vitro and in vivo techniques. During this period, work will also have commenced on the design of the process chemistry that will initially be used to manufacture trial batches of the substances (the active ingredients) for use in the subsequent clinical trials and eventually for full-scale manufacture. In parallel, work will begin on the potential “ druggability ” 56 of these substances, i.e . can the active ingredient be converted into a form that could be taken by a patient such that the substance can interact with the target. This is by no means a straightforward task. The ideal pharmaceutical from the perspective of the patient is a tablet taken once a day. Any departure from this ideal has an adverse impact on adherence, i.e. the likelihood that the patent will actually adhere to the treatment regime. However, if, for example, you need the pharmaceutical to be absorbed in the intestine, you have to ensure that it is able to pass though the highly acidic conditions in the stomach without being degraded, which can be a challenging problem. 57 At the end of all this activity it is possible that a candidate drug, and potentially a reserve candidate, will have emerged. The reserve candidate is usually the second best candidate to emerge at this point and is the one that can be taken forward rapidly to replace the lead candidate should any unexpected problems arise during the clinical trials.