Realising lead-oriented synthesis

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The pharmaceutical industry is the UK's third largest exporting sector, annually contributing £17bn to exports, and investing £4.5bn in UK research and development. The pharmaceutical industry is, however, dogged by a high failure rate (around 97%) of drug candidates, often late in the drug discovery process. A reduction in the failure rate of drug candidates would revolutionise the pharmaceutical industry (for example, a reduction in the rate of failure to even 94% would double the number of successful drugs).The drug discovery process often begins with the screening of many (typically at least hundreds of thousands) molecules for a required biological function. Unfortunately, the active molecules identified in the high-throughput screening process are not optimised drug molecules; instead, these molecules (known as "leads") are starting points for optimisation to give final drug molecules.There is now a clear link between the physical properties of drug candidates and their probability of successfully negotiating the development process to yield marketed medicines. In turn, the properties of drug candidates are often dependent on those of lead molecules. Unfortunately, enhancement of corporate screening collections of molecules is hampered by the poor availability of large numbers of compounds with appropriate lead-like physical properties. A recent analysis of 4.6 million commercially available compounds revealed that less than 1% had optimal lead-like properties. Furthermore, emerging synthetic methods are not, in large part, addressing this deficiency: in 2009 papers in key synthetic organic chemistry journals, only 1.8% of prepared compounds (249 from 13454) had lead-like properties. The development of robust synthetic methods for preparing diverse and novel lead-like molecules remains a significant and unmet academic challenge.This project will realise a new approach to synthetic chemistry - lead-oriented synthesis - which will focus on the preparation of large numbers of diverse small molecules with lead-like physical properties. The project will specifically focus on the development of a systematic approach to the synthesis of diverse families of novel molecular scaffolds with designed 'lead-like' properties. Crucially, specific methods will only be optimised when it has been established that the requirements of lead-oriented synthesis are directly addressed. The project will involve the identification, optimisation and demonstration of the power of a toolkit of reactions that enable the synthesis of large numbers of diverse, lead-like molecules. Realising the full value of the research will require not only the successful execution of the approach, but the definition of a mechanism by which the technology can be made commercially available to end-users (in the pharmaceutical, and other discovery-based, industries). We have engaged, and will continue to engage, with end-users to ensure that the outputs of the project meet their specific requirements. The systematic approach will address the poor availability of lead-like compounds to end-users; will improve the physical properties of starting points and, hence, drug candidates; and will increase the probability of drug candidates negotiating the development process to become marketed medicines.