High-throughput screening for lead optimization: a rational approach

Curr Opin Drug Discov Devel. 2000 Jan;3(1):63-71.


Genetics, combinatorial chemistry and automation have greatly increased the number of therapeutic programs and compounds in the pharmaceutical industry pipeline. The increase in the number of new molecular entities (NMEs) has led to changes in the process by which compounds are evaluated during drug discovery and selected for clinical development. There is a need for the earlier determination of the absorption, distribution and elimination characteristics of NMEs, and drug metabolism scientists are working to develop higher-throughput in vitro screens for absorption, distribution and metabolism of compounds. These screens rely on advancements in analytical technology and molecular biology, and frequently use human or 'humanized' tissues. Throughput to determine in vivo pharmacokinetics has also progressed with the use of mixture dosing and sample pooling methods. The continued refinement of in vitro and in vivo ADME methods will allow the industry to evaluate the absorption and disposition characteristics of larger numbers of molecules and will ultimately allow the prediction of human pharmacokinetics at early stages of the development process.