Amide Hydrolysis of a Novel Chemical Series of Microsomal Prostaglandin E Synthase-1 Inhibitors Induces Kidney Toxicity in the Rat

Abstract

A novel microsomal prostaglandin E synthase 1 (mPGES-1) inhibitor induced kidney injury at exposures representing less than 4 times the anticipated efficacious exposure in man during a 7-day toxicity study in rats. The findings consisted mainly of tubular lesions and the presence of crystalline material and increases in plasma urea and creatinine. In vitro and in vivo metabolic profiling generated a working hypothesis that a bis-sulfonamide metabolite (determined M1) formed by amide hydrolysis caused this toxicity. To test this hypothesis, rats were subjected to a 7-day study and were administered the suspected metabolite and two low-potency mPGES-1 inhibitor analogs, where amide hydrolysis was undetectable in rat hepatocyte experiments. The results suggested that compounds with a reduced propensity to undergo amide hydrolysis, thus having less ability to form M1, reduced the risk of inducing kidney toxicity. Rats treated with M1 alone showed no histopathologic change in the kidney, which was likely related to underexposure to M1. To circumvent rat kidney toxicity, we identified a potent mPGES-1 inhibitor with a low propensity for amide hydrolysis and superior rat pharmacokinetic properties. A subsequent 14-day rat toxicity study showed that this compound was associated with kidney toxicity at 42, but not 21, times the anticipated efficacious exposure in humans. In conclusion, by including metabolic profiling and exploratory rat toxicity studies, a new and active mPGES-1 inhibitor with improved margins to chemically induced kidney toxicity in rats has been identified.

The Impact of Solute Carrier (SLC) Drug Uptake Transporter Loss in Human and Rat Cryopreserved Hepatocytes on Clearance Predictions

“…Chemicals were purchased from Sigma-Aldrich (St. Louis, MO) unless otherwise specified. A series of AstraZeneca (AZ) project compounds, including microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors [chemical structures are presented in Bylund et al (2013)], was obtained from AstraZeneca's compound collection.…”

“…Measuring in vitro metabolic stability for four close chemical analogs from an AstraZeneca series of mPGES-1 inhibitors showed that they displayed similar in vitro metabolism patterns: rapid metabolism in metabolic stability assays by human microsomes but stable when incubated with human cryopreserved hepatocytes [a representative example is shown in Table 2 and Fig. 7; structures are published by Bylund et al (2013)]. No active uptake was indicated in human cryopreserved hepatocytes using the media loss method, as the decrease in extracellular concentration seen when incubating cryopreserved cells and compound closely corresponded to the binding seen when incubating compound with dead hepatocytes (Fig.…”

Ligand‐based Modeling for the Prediction of Pharmacophore Features for Multi‐targeted Inhibition of the Arachidonic Acid Cascade

“…This is a promising finding since the acidic mPGES‐1 inhibitors have several drawbacks including toxicity, loss of efficiency in vivo and non‐selectivity . These have been attributed to toxic metabolites formed by amide hydrolysis and cross‐reactivity with cyclooxygenase (COX) enzymes ,. In contrast, Rorsch et al (2010) identified a non‐acidic benzamide molecule which inhibits mPGES‐1 with an IC50 of 0.5 μM and has no inhibitory effect on the COX enzymes .…”

Targeting eicosanoid pathways in the development of novel anti-influenza drugs

“…Furthermore, survival post-myocardial infarct was reduced in celecoxib-treated WT mice (60% survival) in comparison to vehicletreated control WT mice (100% survival) or Ptges -/-mice (100% survival) [44]. In another study, treatment of rats with the mPGES-1 inhibitor AZ'7847 induced kidney injury, which was associated with the propensity of the inhibitor to undergo amide hydrolysis [45]. This observation led the authors to identify another potent mPGES-1 inhibitory compound (AZ'0908) with low propensity for amide hydrolysis and treatment of rats with this compound revealed minimized toxicity [45].…”

“…In another study, treatment of rats with the mPGES-1 inhibitor AZ'7847 induced kidney injury, which was associated with the propensity of the inhibitor to undergo amide hydrolysis [45]. This observation led the authors to identify another potent mPGES-1 inhibitory compound (AZ'0908) with low propensity for amide hydrolysis and treatment of rats with this compound revealed minimized toxicity [45]. Together, these studies demonstrate the potential safety of mPGES-1 inhibition compared to COX inhibition.…”