Modulating metabolism

There is no doubt that one of the largest challenges facing industry-based medicinal chemists today is that of modifying the metabolism of a lead structure to enhance the latter's overall PK profile, usually within the context of trying to prevent or attenuate a given metabolic event so as to prolong biological half-life. Numerous texts,250 monographs,251,252 and reviews253,254 are available for readers interested in taking up this particular call for medicinal chemistry input. Focusing upon phase 1 metabolic pathways, the most aggressive and thus also the most frequently encountered biotransformation reactions are depicted in Figure 15 relative to chemical functionality typically present within a drug molecule. Short of removing the susceptible functionality altogether, the most reliable approach that can be taken to avoid these pathways is that of introducing steric hindrance either directly into that site or into as close a neighboring position as possible. Although numerous exceptions can be cited, no other physicochemical property comes close to being even a distant second in terms of its successful manipulation in this regard. Thus, given today's fondness within the drug discovery community for simple numerical-related theorems, the aforementioned steric-hindrance strategy can be thought of as 'drug metabolism's rule of one.'

Focusing upon phase 2 metabolic events, two pathways take on prominence, i.e., when such functionality is present, these particular events have a high likelihood of occurring. These two pathways are also depicted in Figure 15 and, in perfect accord with 'drug metabolism's rule of one' can again almost always be counted on to be highly susceptible to steric hindrance. The glutathione detoxification pathway is also a rapid phase 2 biotransformation reaction but since it

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