Pharmaceutical profiling assays generate much useful data that contributes to the lead optimization process in early drug discovery. The solubility, permeability, and metabolic stability of compounds need to be optimized simultaneously with potency, functional activity, cellular activity, selectivity and other biological parameters. However, the data from all of these assays for the numerous compounds prepared by parallel synthesis makes the interpretation of results challenging. The use of multivariate data analysis and design of experiments software helps in the effective utilization of all data in the optimization process.
Many assays for physical properties related to ADME have been introduced into the research efforts of pharmaceutical companies. Because ADME issues have been responsible for many failures of drug candidates in the development stage, the trend in industry has been to move assays predictive of later ADME issues earlier into the discovery stage. If properties related to ADME can be optimized earlier in the discovery process, it is hoped that there will be fewer failures at the development stage. Assays for physical properties of importance for good levels of oral absorption such as solubility and permeability, as well as assays to assess metabolic stability and interaction with CYP enzymes can now be run in medium or high throughput modes, yielding information on all new compounds synthesized for lead optimization programs. In addition to yielding information related to ADME, these data are also useful for optimizing properties for earlier phases of testing, such as enzyme assays, cellular assays, and in vivo models. When run in a high throughput mode, generally only single point data are generated. However, this type of data is useful when looking at trends within series of compounds. Taken together, the data from these assays is termed the pharmaceutical profile of a compound. Five assays make up the standard pharmaceutical profile at Wyeth (Kerns and Di, 2003; Di and Kerns, 2003). These include solubility, permeability, blood brain barrier permeability, microsomal stability, and cytochrome P450 inhibition. Each of these assays will be described in more detail below.
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