Metabolically labile drugs

As described previously, the presystemic metabolism of drugs may occur via various mechanisms. It is obvious, therefore, that coadministration of a low bioavailable drug and its metabolism inhibitor, which can selectively inhibit any of the contributing processes, would result in increased fractional absorption and hence a higher bioavailability. In fact, this approach seems to be a promising alternative to overcome the enzymatic barriers to oral delivery of metabolically labile drugs such as peptides and proteins. 

Metabolic activity may also constitute a considerable biochemical barrier to drag absorption. As described above, extensive enzymatic degradation of labile drugs in the gastrointestinal tract can severely limit their oral bioavailability. Other routes (nasal, buccal, transdermal etc.) are currently undergoing intensive investigations as possible sites of drug entry, partly, indeed often primarily, because these routes have lower enzymatic activity than the oral route and can avoid first-pass effects. 

Drug moieties absorbed via the oral epithelium are delivered directly into the blood, avoiding first-pass metabolism effects of the hver and gut wall. Thus oral mucosal delivery may be particularly attractive for the delivery of enzymatically labile drugs such as therapeutic peptides and proteins. 

Often these types of experiments can point to the portion of the drug that has been metabolically altered, rather than completely identify the structure of the metabolite itself However, as mentioned previously, this is often enough in the discovery phase to alert the structural chemists to the metabolically labile portion of the molecule, but sometimes further experiments... 

The lead 4 for delavirdine (6) was discovered in a screened set of 1,500 computationally diverse representatives of the Upjohn compound collection. There is only one literature ref." to the delavirdine lead structural type, exemplified by compound 7, prior to the disclosure of RT inhibitory activity for this class. Rapid SAR expansion of the lead was enabled by /V-benzyl connectivity and many alkylated and acylated variations of the upper portion of the piperazine scaffold were explored. Ultimately the acylindole, initially bearing a 5-methoxy substituent as in the first clinical candidate atevirdine (5), emerged as preferred. This was found to be metabolically labile and was subsequently replaced with the methylsulfonamide group. Early work also identified the /V-ethyl substituent of the lead as a potential metabolic liability and, although this pattern was retained in the first clinical candidate, it was replaced by the A-isopro-pyl substituent in the approved drug, delavirdine (6). 

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. 

Metabolism studies play an important role in the drug discovery and development process (Borchardt et al., 1998 Liu and Hop, 2005 Naganeo and Iwasaki, 2004 Baillie, 2004 Hop, 2004 Korfmacher, 2003, 2005). The metabolite characterization of a new chemical entity (NCE) in various drug discovery stages is crucial in assessment of the safety of a drug for human use. The identification of metabolites may reveal the metabolically labile portions of a molecule in a particular drug series. This information can be used by the synthetic chemists to synthesize compounds that are less susceptible to metabolism and, consequently, have a lower elimination rate and a longer... 

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