The Choice of Bioassay The Compound Progression Path

The challenge for drug discovery scientists is clear. Although the current medicinal chemistry-driven drug discovery process is often represented as a linear stepwise series of events (Figure 4.4), in practice, the process is holistic and iterative insofar as changes in structure impact all the properties of an NME (Figure 4.5). The simplest most functionally reduced assays usually involve the measurement of the primary interaction between the compound and its site of action. The assay readout from these basic or primary assays is usually a measure of the affinity of the compound for the drug target expressed in terms of the equilibrium dissociation constant, which is the concentration of the compound that occupies half the sites. For both the pharmacologist and medicinal chemist, these assays are perhaps the most satisfying. The assays are usually associated with low variance, and because the activity of the compounds can be expressed by the single chemical affinity parameter, the communication of progress of medicinal chemistry is straightforward. The functionally reduced assays are cheaper and faster, allowing the testing of many compounds in a time frame commensurate with the medicinal chemist's ability to conceive and synthesize new molecules based on the assay results. The problems begin to emerge when the chemist tries to address other properties of a potential NME-those governing the ADMET properties. These require the employment of the increasingly complex, expensive, and time-consuming intact physiological systems from

Gene product selected as potential target

Pathway analysis, gene knockouts etc. used to investigate the potential impact of manipulating the target

Robust primary bioassay established and validated

Chemical libraries screened for primary activity

Confirmation of compounds biopharmaceutical properties

Medicinal chemistry optimizes properties

Efficacy established in animal disease models

Safety margins established in animals

Safety & efficacy established in patients

Product with regulatory approval

----Target identification

Target validation Assay development High-throughput screen Lead compound generation

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