The Contribution of Combinatorial Chemistry to Lead Generation: An Interim Analysis

In the process of finding new drug candidates, medicinal chemists nowadays have a variety of options to choose from, one is to apply combinatorial chemistry techniques. Since the early 1990's synthetic and analytical methods as well as new technologies have been growing rapidly in the area of combinatorial chemistry. Applying these techniques has resulted in the production of large numbers of compounds. A trend is observed towards smaller libraries of compounds with more drug-like properties. An analysis is made to establish the contribution of combinatorial chemistry in providing new lead candidates for (pre-)clinical development towards new pharmaceutical products. Eleven representative examples are given to describe the impact of combinatorial chemistry on different levels of the lead discovery and optimization process. Furthermore, reports on combinatorial chemistry products that are already in (pre) clinical development were traced back to their source. The interim analysis showed only limited success of early combinatorial chemistry approaches in terms of delivering lead candidates. Second generation libraries appear to be more drug-like and focussed and may result in more compounds entering clinical development in the future.