Protocol development, library design

Effectiveness of ADME (absorption, distribution, metabolism, excretion) design implementation depends on whether chemistry protocol development or chemistry production is rate determining. If chemistry production is rate determining there will be excess validated protocols relative to library production. This means that protocols can be prioritized as to their ADME attractiveness and the least attractive protocols from an ADME perspective may never be translated into actual library production. However, protocol development and not library production is often the rate-determining step. This eventuality is unfortunate because there is an understandable reluctance to discontinue chemistry synthetic efforts because of a poor ADME experimental profile if considerable chemistry... 

If protocol development is rate determining, the effectiveness of ADME experimental assays depends very much on how the early exemplars are synthesized. In theory, the most effective method would be to obtain a well-spaced subset of the library in an experimental design sense. A traditional, noncombinatorial, synthesis would accomplish this but would not fit in well with a combinatorial optimization process. A possible means around this problem is to institute some type of early automated clean-up of combinatorial exemplars from partially optimized reaction schemes. This is not a tidy solution because the most efficient process would be an automated clean-up on the entire library after the optimization process was complete. 

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