Electrochemically Simulated Oxidative Metabolization Pattern of Neurokinin-1 Antagonist Aprepitant

Considering the scarcity of data regarding the electrochemical behavior of neurokinin-1 (NK1) antagonists, the electrochemical oxidation pathways of one of the class representatives, aprepitant, were investigated. The development of drugs capable of blocking NK1 receptors brought into light several new potential therapeutic applications, therefore the elucidation of their oxidative metabolic pathway aiding in completing the picture of the observed pharmacological activity is desired. For the simulation of the human microsomal oxidation of aprepitant, a mechanistic study in an EC/MS setup using a thin-layer flow-through electrolytic cell based on a boron-doped diamond working electrode on the range of 0 – 2500 mV vs Pd/H2 was performed. Potential isomers of electrochemically generated species, previously unknown oxidative products and collision induced ionic fragments were identified by LC-MS analysis and confirmed by MS2 fragmentation, establishing a correlation pattern between the formerly reported in vivo and in vitro metabolites and the electrochemically generated ones.