Structure−Activity Relationships for the Degradation Reaction of 1-β-O-Acyl Glucuronides. Part 3: Electronic and Steric Descriptors Predicting the Reactivity of Aralkyl Carboxylic Acid 1-β-O-Acyl Glucuronides

Abstract

Since 1-beta-O-acyl glucuronides (betaGAs) are thought to be chemically reactive metabolites capable of binding to tissue proteins, possibly leading to adverse drug reactions of the parent carboxylic acid drugs, we have initiated research efforts to derive structure-activity relationships (SARs) of betaGAs, with a focus on finding appropriate descriptors that predict their intrinsic electrophilic reactivity or degradation rate constants (k values). Our previous SAR studies on the k values of betaGAs derived from o-, m-, and p-substituted benzoic acids demonstrated that the diversity and complexity of the k values were controlled by the electronic and/or steric effects of the parent carboxylic acids. In the present study, we performed further SAR studies on the k values of 13 betaGAs derived from aralkyl carboxylic acids, focusing on the substituents and stereochemistry at the alpha-position of the parent carboxylic acids. In single regression analyses, the pKa and (1)H NMR chemical shifts (delta(COOH)) of the parent carboxylic acids correlated well with the log k values of seven betaGAs derived from five arylacetic and two (R)-2-arylpropionic acids, whereas the (13)C NMR chemical shifts [delta(C horizontal lineO) and delta((C horizontal lineO)OH)] correlated with the log k values of another seven betaGAs derived from the five arylacetic and two (S)-2-arylpropionic acids. Excellent correlations were also obtained between the log k values of four betaGAs with a common 4-phenylbenzyl moiety and the partial atomic charges (natural type) of the corresponding carboxylic hydrogen atoms (Hpac), the molar volume (MV), and the molar refractivity (MR). In multiple regression analyses, appropriate combinations of electronic (delta(COOH) or pKa) and steric [Taft's steric constant (Es) or delta((C horizontal lineO)OH)] descriptors could predict the log k values of betaGAs; electron-withdrawing 1-beta-O-acyl groups increased the k values, while increasing steric hindrance around the linkages decreased them. The standard partial regression coefficients indicated that the steric effects of the 1-beta-O-acyl groups of betaGAs affected the k values as strongly as the electronic effects. External validation of the derived SAR models is also discussed.

The Generation, Detection, and Effects of Reactive Drug Metabolites

“…More recently, Baba and Yoshioka have also extended their studies to phenylacetic acids and concluded that a blend of p K a values, 13 C chemical shifts of the migrating C=O and Taft's steric factors gave good predictivity of half‐lives in multiple regression analysis. There were differences, however, between their predicted k values for phenylacetic acid AGs and those measured in the abovementioned study: moreover, the predicted favorable TS from this study for 10 (R) is actually the higher energy TS2 of Figure .…”

In silico prediction of acyl glucuronide reactivity

“…Correlations have been established between the 13 C NMR carbonyl shift and AG reactivity for small series' of model benzoic acids and arylalkyl carboxylic acids [11,12,24]. Figure 4a and b showed that for our set of methyl esters, measured 13 C NMR is correlated with reactivity explaining approximately 60% of the variance.…”

“…Interestingly, no further electronic parameters other than calculated 13 C NMR shift were significant in the final model. The work of Yoshioka and Baba highlighted use of the pK a , calculated partial atomic charge on the acidic proton of the parent acid, and proton and carbonyl NMR chemical shift as important electronic descriptors of AG reactivity depending on the sub series studied [12,24]. Interestingly Yoshioka found that 13 C carbonyl shift correlated with other steric rather than electronic parameters.…”

Role of Metabolism in Toxicity of Drugs in Humans

“…Acyl glucuronides of ibufenac and other acetic-acid-based NSAIDs such as tolmetin and zomepirac, all of which have been withdrawn due to toxicity, exhibit the highest level of rearrangement and covalent binding, whereas mono-α-substituted acetic acids (2-substituted propionic acids) such as ibuprofen and naproxen exhibit intermediate level of acyl glucuronide rearrangement and covalent binding. Overall, these observations imply that inherent electronic and steric properties must modulate the rate of acyl glucuronide rearrangement [71,72]. Thus, in the case of ibuprofen, it is likely that presence of the α-methyl substituent slows the rearrangement of the acyl glucuronide to the electrophilic carbonyl intermediate.…”