Structure metabolism relationships

Balakin KV, Ekins S, Bugrim A, Ivanenkov YA, Korolev D, Nikolsky Y, et al. Quantitative structure-metabolism relationship modeling of the metabolic V-dealkylation rates. Drug Metab Dispos 2004 32 1111-20. 

Buchwald P. Structure-metabolism relationships steric effects and the enzymatic hydrolysis of carboxylic esters. Mini Rev Med Chem 2001 1 101-11. 

Ablstrom, M., Ridderstrom, M., Luthman, K. and Zamora, I. (2007) CYP2C9 structure-metabolism relationships optimizing the metabolic stability of cox-2. Journal of Medicinal Chemistry. 50 (18), 4444-4452. 

This subsection is devoted to the metabolic reactivity of the amide bond in anilides, i.e., compounds whose amino moiety is attached to an aromatic ring. Based on the nature of the acyl moiety, a number of classes of anilides exist, three of which are of particular interest here, namely arylacetamides, acylani-lides, and aminoacylanilides. The first group contains several analgesic-antipyretic drugs, the second A4-acyl derivatives of sulfonamides, and the third a number of local anesthetics. Particular attention will be paid to structure-metabolism relationships in the hydrolysis of these compounds. Cases where hydrolysis leads to toxification will be summarized in the last part of the chapter. 

One of the most actively investigated aspects of the biohydrolysis of carboxylic acid esters is enantioselectivity (for a definition of the various stereochemical terms used here, see [7], particularly its Sect. 1.5) for two reasons, one practical (preparation of pure enantiomers for various applications) and one fundamental (investigations on the structure and function of hydrolases). The synthetic and preparative aspects of enantioselective biocatalysis by hydrolases have been extensively investigated for biotechnology applications but are of only secondary interest in our context (e.g., [16-18], see Sect. 7.3.5). In contrast, the fundamental aspects of enantioselectivity in particular and of structure-metabolism relationships in general are central to our approach and are illustrated here with a number of selected examples. 

Series of homologous esters have been investigated to try to establish structure-metabolism relationships, however partial and limited the latter may be. This aspect will be discussed again in the context of prodrugs (Chapt. 8). Here, we mention a few representative studies in which model substrates were used. Table 7.2 documents the substrate specificity of a rabbit liver carboxylesterase (ES-1A) toward homologous series of methyl, 4-nitrophenyl, a-naphthyl, /1-naphthyl, and 4-methylumbelliferyl esters [41]. In... 

P. Buchwald, N. Bodor, Quantitative Structure-Metabolism Relationships Steric and Nonsteric Effects in the Enzymatic Hydrolysis of Noncongeneric Carboxylic Esters , J. Med. Chem. 1999, 42, 5160-5168. 

Quantitative Structure-Metabolism Relationships in Prodrug Design... 

In summary, the above discussion illustrates how metabolic data for large series of analogous compounds may be amenable to quantitative structure-metabolism relationships. In ideal cases, such regression equations may even have some predictive power and can lead to mechanistic insights. 

In summary, (oxodioxolyl)methyl esters of carboxylic acid drugs appear to be generally useful as prodrugs. However, more studies are needed to document the structure-metabolism relationships, the relative contribution of enzymatic vs. nonenzymatic reactions in their in vivo activation, the reasons of some failures, their toxic potential, and their pharmacokinetic behavior in humans. 

There are comparatively few studies addressing the structure-metabolism relationships of phosphoric acid monoester hydrolysis. For example, kinetics of decomposition in rat whole blood were examined for the phosphoric acid monoesters of estrone, 17a- and 17/J-testosterone, 3-(hydroxyme-thyl)phenytoin (see Fig. 9.7,a), and 1-phenylvinyl alcohol (9.28, the enolic form of acetophenone) [87]. As a general trend, the rate of hydrolysis increased with the acidity of the leaving hydroxylated compound. In other words, hydrolysis was the fastest for the phosphoric acid aryl monoester (estrone 3-phosphate), and slowest for the two testosterone phosphoric acid... 

The data in Table 10.1 suggest that the reactivity of epoxide hydrolase toward alkene oxides is highly variable and appears to depend, among other things, on the size of the substrate (compare epoxybutane to epoxyoctane), steric features (compare epoxyoctane to cycloalkene oxides), and electronic factors (see the chlorinated epoxides). In fact, comprehensive structure-metabolism relationships have not been reported for substrates of EH, in contrast to some narrow relationships that are valid for closely related series of substrates. A group of arene oxides, along with two alkene oxides to be discussed below (epoxyoctane and styrene oxide), are compared as substrates of human liver EH in Table 10.2 [119]. Clearly, the two alkene oxides are among the better substrates for the human enzyme, as they are for the rat enzyme (Table 10.1). 

Similarly, quantitative structure-metabolism relationships (QSMR) have been studied [42]. QSAR tools, such as pattern recognition analysis, have been used to e. g. predict phase II conjugation of substituted benzoic acids in the rat [53]. 

DiCarlo, F.J., Bickart, P. and Auer, C.M. (1986) Structure—metabolism relationships (SMR) for the prediction of health hazards by the Environmental Protection... 

DiCarlo, F.J. (1990) Structure-activity relationships (SAR) and structure-metabolism relationships (SMR) affecting the teratogenicity of carboxylic acids. Drug Metab. Rev.,... 

Chemical metabolism can be described qualitatively or quantitatively. Many scientists can make qualitative predictions of the likely excretion products or blood plasma metabolites in mammals, or a particular animal including man, based on accumulated knowledge and experience. Such knowledge, in its raw form, generally consists of structure-metabolism relationships that are frequently expressible as qualitative structure-based rules that may be encoded into computer-based expert systems (see Chapter 9 for a full definition). Examples of such systems, in their more fully developed commercial forms, are discussed toward the end of this chapter. 

Many studies predicting metabolism have concentrated on quantitative aspects (e.g., relating the rate characteristics or proportion of a particular metabolic reaction to the experimental or calculated properties of a molecule), or the characterization of the structural requirements (i.e., structure-metabolism relationship for a particular enzyme or class of enzyme). 

For the metabolism of the molecule X (see Figure 10.5) used as in a recent comparison of several structure-metabolism relationship database systems (Wilbury, 1999), META produced the following pathways and rate priority numbers (in brackets) ... 

Cupid, B.C., Beddell, C.R., Lindon, J.C., Wilson, I.D. and Nicholson, J.K., Quantitative structure-metabolism relationships for substituted benzoic acids in the rabbit prediction of urinary excretion of glycine and glucuronide conjugates, Xenobiotica, 26, 157-176, 1996. 

Scarfe, G.B., Wilson, I.D., Wame, M.A., Holmes, E., Nicholson, J.K., and Lindon, J.C., Structure-metabolism relationships of substituted anilines prediction of N-acetylation and N-oxanilic acid formation using computational chemistry, Xenobiotica, 32, 267-277, 2002. 

Cruciani, G., Pastor, M., Clementi, S., dementi, S. GRIND (GRID independent descriptors) in 3D structure-metabolism relationships, in Rational Approaches to Drug Design, Hoitje, H.D. and SippI, W. (eds.), Prous Science Press, Barcelona, 2001, pp. 251-260. 

Ahlstrom MM, Ridderstrom M, Zamora I, et al. CYP2C9 structure-metabolism relationships Optimizing the metabolic stability of COX-2 inhibitors. / Med Chem. 2007 50(18) 4444-4452. 

Quantitative structure metabolism relationships (QSMR) were pioneered by Hansch and coworkers [13-16] using very small sets of similar molecules and... 

---