Figure 1. Research budget (billion $) and total number of US drug registrations in 2003. Figure 2. Reasons for stopping clinical development of 121 compounds in clinical trials carried out by seven British find more companies. PK, pharmacokinetics First, the original hypothesis may be wrong, and the end result is a

useful experiment, albeit a very expensive one. Second, and this is perhaps just as likely, the animal models may not represent the tests used in phase I and phase II clinical trials Inhibitors,research,lifescience,medical – it is also possible that the tests used in phase I and II do not represent the true patient response. Indeed, of the 340 compounds entering phase I per year, four out of five fail, and even when registration is achieved, less than half of the compounds recoup their development costs. Inhibitors,research,lifescience,medical The failure of drugs to work in the clinical setting

(lack of efficacy due either to the concept not working, or to the animal models or the clinical models not responding to the patients’ needs) is a key area for improvement. Third, increasing safety requirements discourages risk. This is particularly the case for CNS-active drugs which may have cardiovascular side effects (effects on electrocardiographic [ECG] QTc intervals for example). It remains a truism that no drug can be effective without having some measure ofri.sk. However, it is now possible to have high-throughput screens for safety, and to do a better job of selecting compounds Inhibitors,research,lifescience,medical at an early stage. The difficulties faced by a drug discoverer are shown by the sequence below. First, he or she must find Inhibitors,research,lifescience,medical the optimal structure/activity, then exclude structure/activity at other sites: Definition of structure/activity at site of action Exclusion of structure/activity at cytochromes Exclusion of structure/activity

– mutagenicity Exclusion of structure/activity – cardiac QTc Start of toxicity studies. Fourth, there is the realization of the increasing complexity of biological systems. Although there may be only 25 000 to 30 000 genes, many of which are drug Inhibitors,research,lifescience,medical targets (Figure 3) , the gene products are much more complex because of alternative splicing, mRNA editing, receptor dimerization, functional trafficking (where drugs acting at the same receptor may have different effects) and the multiple post-translational controls and accessory proteins. Figure 3. Signaling genes in the human genome. New Cell press technological opportunities In vitro screening Screening on recombinant proteins has proven to be immensely powerful, and can provide new leads from high-throughput screening on a scale which would be impossible with other technologies. Now the target proteins may even be crystallized, with the drug, or even with fragments of the drug, and the crystals analyzed to define the conformational changes induced in the target by different drugs. The throughput of this technology is such that entire chemical scries can be analyzed for their direct effects on the protein of interest.