In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

摘要

The drug discovery process can be accelerated by chromatographic profiling of the analogs to model in vivo distribution and the major non-specific binding. A balanced potency and chromatographically determined membrane and protein binding (IAM MB/PB) data enable selecting drug discovery compounds for further analysis that have the highest probability to show the desired in vivo distribution behavior for efficacy and reduced chance for toxicity. Although the basic principles of the technology have already appeared in numerous publications, the lack of standardized procedures limited its widespread applications especially in academia and small drug discovery biotech companies. In this paper, the standardized procedures are described that has been trademarked as Regis IAM MB/PB Technology®. Comparison between the Drug Efficiency Index (DEI=pIC50-logVdu+2) and generally used Ligand Lipophilicity Efficiency (LLE) has been made, demonstrating the advantage of measured IAM and HSA binding over calculated log P. The power of the proposed chromatographic technology is demonstrated using the data of marketed drugs.