Acyl Glucuronidation and Acyl‐CoA Formation Mechanisms Mediating the Bioactivation and Potential Toxicity of Carboxylic Acid‐containing Drugs

Acyl Glucuronide and Coenzyme A Thioester Metabolites of Carboxylic Acid-Containing Drug Molecules: Layering Chemistry with Reactive Metabolism and Toxicology

“…The extent of reactivity, though, depends on the structure of the drug molecule; it is generally believed that greater steric hindrance in proximity of the glucuronic acid conjugate helps to stabilize the metabolite . Reactions of acyl glucuronides can be categorized as follows: (1) hydrolysis, (2) acyl migration, and (3) direct reaction with macromolecules . The stability half-life ( t 1/2 ) represents the loss of 1-β- O -acyl glucuronide via a combination of hydrolytic and acyl migration pathways …”

“…20 Reactions of acyl glucuronides can be categorized as follows: (1) hydrolysis, (2) acyl migration, and (3) direct reaction with macromolecules. 19 The stability half-life (t 1/2 ) represents the loss of 1-β-O-acyl glucuronide via a combination of hydrolytic and acyl migration pathways. 15 Hydrolysis involves the reaction of water at the ester carbonyl, resulting in the release of the original aglycone and the drug molecule (Figure 2).…”

“…The final product of drug conjugation of coenzyme A (CoA) is a thioester: the obligate precursor step of this metabolic pathway is the activation of the carboxylic acid to a monophosphate (Figure 6) by reaction of the drug with adenosine triphosphate (ATP), 34 studies of hydrolysis with acyl CoA thioesters of salicylic acid, benzoic acid, and 2-fluorobenzoic acid (hydrolysis rates of 0.5, 0.3, and 0.3% per minute, respectively) indicated the potential contribution of structural moieties such as hydrogen bonding between the neighboring hydroxyl group and the carbonyl oxygen of salicylic acid and the lack of electron-withdrawing effects in 2-fluorobenzoic acid. 19,35 Similarly, the high stability of the acyl CoA thioester of clofibric acid in pH 7.5 buffer at 37 °C (21 h) may be attributed to the presence of the bulky methyl groups on the carbon α to the thioester carbonyl. 36 In another example of effects of neighboring groups, the acyl CoA thioester of 2,4-dichlorophenoxyacetic acid degraded at a rate of 9%/h compared to the much greater stability of the related compound phenylacetic acid, presumably due to the electronic effects exerted by the β-oxygen and the ortho-and para-chlorine substitutions that make the ester carbonyl more electrophilic in the former.…”

“…A complementary strategy, proposed to be applied during Ph1 and Ph1/2 clinical studies, focuses on circulating levels of acyl glucuronide across species . Importantly, while acyl glucuronides generally get more attention for derisking, it is important that early discovery paradigms investigate acyl CoA thioester pathways as well . Much focus has been given to early structure–activity relationship interventions using bulky substituents that impact the electrophilicity and steric environment of the ester or thioester carbonyl.…”

“…18 Importantly, while acyl glucuronides generally get more attention for derisking, it is important that early discovery paradigms investigate acyl CoA thioester pathways as well. 19 Much focus has been given to early structure−activity relationship interventions using bulky substituents that impact the electrophilicity and steric environment of the ester or thioester carbonyl. Computational models have also been explored to guide medicinal chemistry efforts in early drug discovery.…”