Realising lead-oriented synthesis

制药业是英国第三大出口行业，每年出口贡献170亿英镑，并在英国研发方面投资45亿英镑。然而，制药行业被候选药物的高失败率（约97%）所困扰，通常是在药物发现过程的后期。降低候选药物的失败率将彻底改变制药工业（例如，将失败率降低到94%将使成功药物的数量增加一倍）。药物发现过程通常从筛选许多（通常至少数十万）分子以获得所需的生物学功能开始。不幸的是，在高通量筛选过程中发现的活性分子并不是优化的药物分子；相反，这些分子（被称为“先导”）是优化最终药物分子的起点。现在，候选药物的物理特性与它们在开发过程中成功谈判以生产上市药物的可能性之间存在明确的联系。反过来，候选药物的性质往往取决于铅分子的性质。不幸的是，由于缺乏大量具有适当的类铅物理性质的化合物，企业筛选分子集合的能力受到阻碍。最近一项对460万种市售化合物的分析显示，只有不到1%的化合物具有最佳的类铅特性。此外，新兴的合成方法在很大程度上并没有解决这一缺陷：在2009年发表在关键合成有机化学期刊上的论文中，只有1.8%的合成化合物（13454篇中的249篇）具有类似铅的性质。发展强大的合成方法来制备多样化和新颖的类铅分子仍然是一个重大的和未满足的学术挑战。该项目将实现一种新的合成化学方法——铅取向合成——它将专注于制备大量具有类似铅的物理性质的不同小分子。该项目将特别侧重于开发一种系统的方法来合成不同家族的新型分子支架，这些分子支架具有设计的“类铅”特性。至关重要的是，特定的方法只有在确定了铅取向合成的要求得到直接解决时才会被优化。该项目将涉及识别、优化和演示一系列反应的能力，这些反应可以合成大量不同的类铅分子。实现研究的全部价值不仅需要成功地执行该方法，还需要定义一种机制，通过这种机制，该技术可以向最终用户（在制药和其他基于发现的行业）商业化。我们已经并将继续与最终用户接触，以确保项目的产出符合他们的具体要求。系统化的方法将解决最终用户难以获得类铅化合物的问题；将改善起始点的物理性质，从而改善候选药物；并且将增加候选药物在开发过程中谈判成为上市药物的可能性。

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.