Drug Metabolism and Discovery Screening Sequences

The development of higher throughput approaches in ADME studies is driven by the advances in high-speed chemistry and pharmacological screening [3], a view of the future where many more compounds would need to be screened, and the availability of the technology. Departments of Drug Metabolism and Pharmacokinetics in the pharmaceutical industry are organizing themselves for the rapid evaluation of large numbers of compounds [4-8]. Higher throughput can move a screening approach up the traditional sequence, provide more comprehensive data on a single compound, or just screen more compounds or even files. The pre-ADME days of Discovery had screening sequences based on an in vitro functional response often followed by an oral rodent pharnmacodynamic model. The advent of ADME, cloned receptors etc., has led to the hierarchical sequence shown in Figure 10.1. Higher throughput could allow a parallel process, which collects large amounts of in vitro pharmacology and ADME data as the primary stage.

The hierarchical model is closest to the traditional approach and meets the needs of a focused, disciplined approach, where molecules are drug-like, with a real possibility of passing some of the ADME criteria. The horizontal model is optimum for looking for exceptions to drug-like property rules and can build SAR streams much

Fig. 10.1 Hierarchical and horizontal in vitro screening sequences. In each phase only compounds possessing certain criteria would move to the next phase. In the hierarchical model

(top) ADME data is collected only on compounds with adequate potency and selectivity. In the horizontal model (bottom) ADME data is collected on all compounds synthesized.

Fig. 10.1 Hierarchical and horizontal in vitro screening sequences. In each phase only compounds possessing certain criteria would move to the next phase. In the hierarchical model

(top) ADME data is collected only on compounds with adequate potency and selectivity. In the horizontal model (bottom) ADME data is collected on all compounds synthesized.

more rapidly so allowing very comprehensive real-time SAR of the type normally reserved for retrospective analysis. These two models indicate a divergence of how the data is handled. The hierarchical model means that full data is available on a few compounds, can be manipulated on a spreadsheet and is within the understanding of a medicinal chemist. This relates to the data being unimportant and the information being retained to drive the process. The horizontal model could result in more than 5000 data points to collate as SAR. This immediately requires computational systems and complex analysis to process and optimize. Some progress has been made in methods used in early ADME evaluation [6] with in silico and higher throughput physicochemical methods being linked to appropriate in vitro models [7]. The next sections give an inventory of some of these approaches.

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