Page - (000341) - in Biomedical Chemistry: Current Trends and Developments

poor pharmacokinetics and/or bioavailability (40%), yet by 2000 this had decreased to less than 10% (Kola & Landis, 2004). This is largely attributable to the advent of in vitro screens for physiochemical properties likely to create downstream liabilities. The placement of these screens early in the pipeline forces compounds with poor solubility, bioavailability, and metabolic stability to fail during far cheaper stages of development and spares the opportunity cost otherwise missed in development of these compounds. Fig. 3.4.6 outlines a generic paradigm for screening compounds. In this paradigm early hits from in vitro activity screens are passed through an absorption, distribution, metabolism, and excretion (ADME) gate before passing into more expensive animal models. The source of compounds could be from commercially available large libraries, libraries of natural product extracts, small scale synthesis, etc. The process remains unchanged. However, feedback from all stages should be iteratively incorporated into the next round of screening. Acceptable physiochemical properties for a drug ultimately depend on the target product profile for intended use; however, it is reasonable to assume that compounds with low solubility or poor permeability may not fit a profile for oral prophylaxis, for example. It should also be noted that many of these properties go hand-in-hand, and that it is often necessary to strike a balance. For example, lipophilicity, permeability, and metabolic instability tend to correlate since CYPs tend to favor lipophilic drugs. From this example, if one were trying to develop a long half-life lipophilic drug to concentrate in the food vacuole of a parasite, it might be necessary to trade off some lipophilicity (and with it potentially some biological activity) to enhance half-life. The subtleties of this interplay of course depend again on the intended use of the drug. Feedback from all stages of screening should be used to inform later rounds. In such a manner, successive rounds of screening should get closer and closer to the desired chemical space with optimum physiochemical properties and biological activity for intended use. From the example of the 8-aminoquinolines, a very modern consideration for drug development arises. Pro-drugs should be fully metabolically characterized, with all pertinent pathways identified. Consideration should be given to the pharmacogenomic make-up of the