The Direct In Vivo Use of Mixture-Based Libraries in the Drug Discovery Process

摘要

Using a mixture-based synthetic combinatorial approach, libraries composed of tens of thousands to millions of different compounds have been produced in a fraction of the time and cost of equivalent individual compound arrays [1,2]. Two approaches have evolved over the past two decades to screen and evaluate the large numbers of compounds now available. These are: 1) the massive parallel screening of large individual compound arrays; and 2) the generation and screening of extremely large, focused mixture-based libraries. The first approach, testing individual compounds, has been successfully utilized for decades to identify useful therapeutics. However, while the use of this method is common in large pharmaceutical companies, it remains impractical for the majority of academic and small research organizations to screen such large numbers of samples. Additionally, the harsh reality is that many drug candidates resulting from combinatorial approaches lack desirable drug-like properties at later stages of testing, thereby suffering a high rate of attrition due to poor physicochemical properties [2]. To circumvent the limitations of existing screening methods, we sought to directly test samples from a mixture-based combinatorial library in vivo for analgesic properties, thereby simultaneously increasing the evaluation of compounds while decreasing the failure rate inherent in the traditional drug discovery process [2]. Previous screening of a library of 400 separate mixtures each of 132,000 hexapeptides by monitoring blood pressure and heart rate in rats and dogs [3] demonstrated the feasibility of this approach, identifying useful therapeutic candidates while simultaneously eliminating compounds with poor absorption, distribution, metabolism and pharmacokinetic properties [3].