Transformation metabolic stability

The development of synthetic methods for the selective introduction of short-chain perfluoroalkyl groups into organic molecules is of interest in drug development [464]. Fluoromodifications often confer unique properties on a molecule, for example in terms of increased metabolic stability and lipophilicity and, as a consequence, the pharmacokinetic profiles are often improved [465]. Burger and coworkers developed a domino process consisting of a SN reaction combined with a Claisen and a Cope rearrangement which allows the transformation of simple fluorinated compounds into more complex molecules with fluoro atoms [466]. Treatment of furan 2-917 with 2-hydroxymethyl thiophene (2-918) in the presence... 

Whether a toxin is naturally reactive to biological macromolecules or receptors, or requires metabolic activation to produce such a species, e.g. the enzyme-mediated transformation of tremorine (9) to the active parasympathomimetic agent oxotremorine (10), it will usually be subject to chemical or enzymic inactivation in vivo. Interruption of the latter process via appropriate substitution may thus lead to an increase in biological activity or toxicity over that of the parent compound. Perhaps the most striking example of this is provided by the extreme metabolic stability and toxicity of TCDD and the nontoxicity of its de- chloro analogue dibenzodioxin (Table 3). 

The retro-peptide bond is a true isosteric peptide bond surrogate and as such may offer an important tool to study topics such as the functional role of the peptide backbone in peptide hormone-receptor interactions, and modulation of metabolic stability and bioavailability. Partially modified retro-inverso-peptides (PMRI-peptides) (e.g., 2-4, 7 Scheme 1) result from a retro-inverso transformation of one or several peptide bonds in an amino- and carboxy-free peptide (e.g., 5 Scheme 1). Evidently, partial or exhaustive retro-inverso transformations result in the introduction of two non-amino acid residues into the... 

Shipkova, P. A., Josephs, J. L., Gmbb, M. F., Langish, A. R., Chen, W., and Sanders, M. (2004). Use of a hybrid linear ion trap/Fourier transform mass spectrometer for determining metabolic stability and metabolite characterization. In Proceedings of the 52nd ASMS Conference on Mass Spectrometry and Allied Topics, Nashville, TN. 

Despite their favourable properties, peptide-based drugs are under-represented in the pharmaceutical market. This discrimination is usually due to their poor bioavailability, which sometimes necessitates non-oral administration or even special medical devices such as inhalers. Another related major disadvantage of peptides is their low metabolic stability due to proteolytic degradation, hi addition, costs of goods for the drug substance are sometimes tremendous. Therefore, there is considerable interest to transform the active principle of biologically active peptides into small molecules with improved pharmacokinetic properties, hi this chapter, we present an overview of... 

In addition to the VolSurf treatment of the GRID fields, the information from the MIF can also be transformed to obtain a pharmacophoric type of representation, which is useful in the modeling of metabolic stability, cytochrome inhibition or even the direct study of the ADME related proteins (Fig. 10.3). The Almond software [17] transforms the MIF into a distance-based representation of the molecule interaction. These parameters describe the geometry of the interaction and QSAR models can be derived where the interaction with a protein is essential. Detailed information on these descriptors is presented elsewhere in this book. 

The GRID MIFs can also be transformed to alignment independent descriptor (GRIND) aimed to give a distance/interaction profile which has proven to be useful in the description of GYP inhibition, metabolic stability and in the active transporter and recognition area. 

The metabolic stability (transformed percentage to 14a) of typical C-6 alkyl ester prodrugs of 14a in liver S9 fractions from rats, monkeys, and humans as well as their pharmacokinetics parameters in rats and monkeys are summarized in Table 3.6. Linear... 

Other ways of looking at hepatic metabolism (e.g. transformed cell lines and liver slices) have a place in drug metabolism studies too, but are less frequently seen early on in drug discovery and won t be discussed here. Instead it s time to tackle the critical issue of how poor metabolic stability, once determined, might be improved. 

The term carbocyclic nucleoside [181] is used to describe a group of compounds structurally related to nucleosides in which the furanose ring has been replaced by a cyclopentane ring. A consequence of this substitution is an enhancement of the metabolic stability of the carbocyclic nucleosides, which are not subjected to the action of nucleoside phosphorylases and hydrolases that cleave normal nucleosides. However, from the conformational point of view the tetrahydro-furan and cyclopentane rings are similar. Thus, carbocyclic nucleosides may act as substrates or inhibitors of the enzymes that activate (kinases) and transform nucleosides and nucleotides in living cells and incorporate them into DNA. Most approaches to the synthesis of carbocyclic nucleosides begin with the construction of the nucleic acid base from a functionalized cyclopentylamine, which with some exceptions is obtained as a racemic mixture. The medicinal chemistry of carbocyclic nucleosides, as well as the synthesis of the intermediate cyclopentylamines have been reviewed [181]. This section deals only with work published after that review, directly related with anti-AIDS research. 

This chapter follows the large-scale MMP analysis paradigm and studies the relationship between molecular transformations and the resulting changes in experimental property, particularly human liver microsomal metabolic stability. More specifically, the ultimate aim has been the identification of metabolic stability isosteres, that is, transformations and replacements with zero or positive effect on metabolic stability. Furthermore, in line with the recent study of Papadatos et al. [18], the possibility of context-dependent isosteric replacements is explored. 

After the generation of the MMPs and the extraction of the transformations, the pairwise property differences were calculated and binned into three bins, indicating the effect of the molecular transformation on the property under examination, namely, favorable (AP>r), unfavorable (AP<—r), and zero effect (-r< APmetabolic stability, a difference of r = 25% was used as the AP threshold. It has to be noted that the metabolic stability measurements refer to % metabolized compound thus, a decrease (i.e., a negative AP) is actually favorable and vice versa. 

Identification of the overall neutral, least detrimental, and least favorable transformations with regard to metabolic stability and identification of interesting isosteres. 

Examination of context sensitivity and exemplification of cases where a certain subset of data does not agree with the average trend of a transformation s effect on metabolic stability. 

Table 6.3 The 20 most frequent transformations found in the metabolic stability data set.

Figure 6.5 Frequency histogram of the 424 most frequent metabolic stability transformations.

With regard to metabolic stability bioisosteric replacements, that is, substituents that are interchangeable with minimal effect on metabolism, one could look at the most neutral transformations, that is, the ones that did not result in a favorable or unfavorable effect on metabolic stability, at least within the defined tolerance threshold of 25%. The substituents of these transformations are therefore, by definition, isosteres. The 12 most neutral transformations in terms of the percentage of examples that led to no significant change are listed in Table 6.4. 

Table 6.4 The 12 most neutral transformations (with >30 examples each) in terms of metabolic stability. 

One may relax the definition of bioisosteres and also include transformations that either maintain or improve metabolic stability. To that end. Table 6.5 lists the 10 least detrimental (top) as well as the 10 least favorable (bottom) transformations in terms of metabolic stability. With regard to the latter, the 10 least favorable transformations can be converted to favorable ones, by reversing the direction of the transformation listed in the table. 

For a long time metabolic stability was thought to be a characteristic of secondary products. Recent experiments, however, have demonstrated that many secondary substances are transformed or are even degraded to compounds of primary metabolism. Three types of secondary compounds may be distinguished with respect to metabolic stability (a) the truely metabolically inert end products, (b) the products stable at a given physiological or developmental state, and (c) the substances undergoing continuous turnover. 

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