In silico prediction of acyl glucuronide reactivity

Abstract

Drugs and drug candidates containing a carboxylic acid moiety, including many widely used non-steroidal anti-inflammatory drugs (NSAIDs) are often metabolized to form acyl glucuronides (AGs). NSAIDs such as Ibuprofen are amongst the most widely used drugs on the market, whereas similar carboxylic acid drugs such as Suprofen have been withdrawn due to adverse events. Although the link between these AG metabolites and toxicity is not proven, there is circumstantial literature evidence to suggest that more reactive acyl glucuronides may, in some cases, present a greater risk of exhibiting toxic effects. We wished therefore to rank the reactivity of potential new carboxylate-containing drug candidates, and performed kinetic studies on synthetic acyl glucuronides to benchmark our key compounds. Driven by the desire to quickly rank the reactivity of compounds without the need for lengthy synthesis of the acyl glucuronide, a correlation was established between the degradation half-life of the acyl glucuronide and the half life for the hydrolysis of the more readily available methyl ester derivative. This finding enabled a considerable broadening of chemical property space to be investigated. The need for kinetic measurements was subsequently eliminated altogether by correlating the methyl ester hydrolysis half-life with the predicted (13)C NMR chemical shift of the carbonyl carbon together with readily available steric descriptors in a PLS model. This completely in silico prediction of acyl glucuronide reactivity is applicable within the earliest stages of drug design with low cost and acceptable accuracy to guide intelligent molecular design. This reactivity data will be useful alongside the more complex additional pharmacokinetic exposure and distribution data that is generated later in the drug discovery process for assessing the overall toxicological risk of acidic drugs.

New Perspectives on Acyl Glucuronide Risk Assessment in Drug Discovery: Investigation of In vitro Stability, In situ Reactivity, and Bioactivation

“…Where pure reference standards of acyl glucuronides are available, NMR based methodologies to detect the disappearance of the anomeric resonance of 1-β-acyl glucuronide [25] or immunostimulation in human peripheral blood monocytes may also serve as a useful surrogate markers of reactivity [44]. In silico approaches such as the partial least squares model proposed by Potter and coworkers [45] can be broadened and qualified to support medicinal chemistry intervention strategies and synthesis of next generation analogs. Another aspect worthy of consideration is that observation of an acyl glucuronide as a ‘major’ metabolic pathway should not preclude progression of a new chemical entity into further development.…”

Impact of Physicochemical Properties on Dose and Hepatotoxicity of Oral Drugs

“…A caveat is the relatively small number of No DILI acidic drugs (15); further data are needed to confirm the lack of a dose effect on the hepato­toxicity of acidic drugs. On the 44 Most DILI acidic drugs, 32 are carboxylic acids, which are prone to reactive metabolite formation via glucuronidation, where the chemical mechanism is well understood . With basic drugs, −p­[MDD] and cLogP have the greatest impact, and Fsp3 is not different between the No DILI and Most DILI groups.…”

Structural investigations of stereoselective profen binding by equine and leporine serum albumins

“…The prolonged use of most NSAIDs leads to gastrointestinal adverse reactions. This was the reason why SUP has been withdrawn from the pharmaceutical market; its use has led to acute renal failure in patients …”