Metabolism-guided structural

The rapid structure identification of metabolites provides an early perspective on the metabolically labile sites or soft spots of a drug candidate [86], This information is useful during lead optimization and can serve to initiate research efforts that deal with metabolism-guided structural modification and toxicity. 

This type of information about a homologous series of drug candidates, when considered in light of the propensity of these compounds to undergo first-pass metabolism and/or liver clearance, allows pharmaceutical scientists to make more intelligent decisions about which compounds to move into animal studies. In addition, when an in vitro-in vivo correlation can be demonstrated for a series of compounds, the results of Caco-2 experiments can be used as a guide by medicinal chemists to make structural modifications to optimize oral bioavailability. 

Information metabolism provides a way to store and retrieve the information that guides the development of cellular structure, communication, and regulation. Like other metabolic pathways, this process is highly regulated. Information is stored by the process of DNA replication and meiosis, in which we form our germ-line cells. These processes are limited to specific portions of the cell cycle. Information is retrieved by the transcription of DNA into RNA and the ultimate translation of the signals in the mRNA into protein. 

Advances in techniques for chemical synthesis allow medicinal chemists to synthesize hundreds to thousands of compounds per month. Metabolic stability screening in liver microsomes is used extensively in early discovery to select the analogs or compounds most likely to have favorable pharmacokinetic parameters. This provides information on the relation of structure to stability, thus guiding synthesis strategies. 

A second-generation compound, (79) (WIN-54954)also advanced into clinical tests, but had disappointing effieacy in Phase II trials, probably beeauseof extensive metabolism. Modifieation of the phenylisoxazole,guided by both structural and metabolic considerations (177), allowed the ereation of a stable and potent antiviral, the third-generation compound (80)(WIN-63 843, pleconaril, or Picovir) (178). This compound was evaluated in Phase III clinical trials and showed efficacy in humans. Oral dosing of virally infected patients with... 

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