Toxicology and Pharmacology Investigation of 2-Phenylaminophenylacetic Acid Derived NSAIDs: Implication of Chemical Structure on Biological Outcomes

Abstract

Diclofenac and lumiracoxib are the most notable 2-phenylaminophenylacetic acid derived non-steroidal anti-inflammatory drugs. Yet, their clinical usage has been associated with toxicities in the liver. While some studies have attributed toxicities to the bioactivation of both drugs to reactive intermediates and the structural predisposition for toxicity has not been elucidated. This pair of compounds presents unique opportunity for a structure-toxicity relationship investigation, given the very subtle change of only a fluoro and methyl group between them. We aimed to address their intricate link by synthesizing compounds that possess the 2-phenylaminophenylacetic acid backbone with varying alkyl and halogen substituents at three positions critical to the COX inhibitory pharmacophore. The synthesized compounds were subjected to in vitro cytotoxicity, pharmacological activity and metabolism testing. The substituents on the three positions were shown to have profound effects on toxicity and pharmacology, with metabolism playing an important role in the toxicity observed. We have provided a better understanding on structure-toxicity-activity-bioactivation relationships and have provided a platform where future investigation can be carried out.