Functional pharmacology: the drug discovery bottleneck?

It is our contention that functional pharmacology, particularly in vivo, must play a greater role in drug discovery if the promises of reductionist techniques are to be brought to full fruition. Despite the advent of high-throughput screening, combinatorial chemistry and informatics, the number of new chemical entities (NCEs) coming on the market has fallen. While the advent of these methodologies makes it possible to move very quickly from molecular target to lead compound, the problem of demonstrating therapeutic utility remains. Has proof of concept (in vivo) become the bottleneck in drug discovery? This article focuses on this problem, and discusses what can be done about it.