Medoxomil Prodrug Strategies

Drug discovery campaigns often face biopharmaceutical challenges, some of which can be solved by a prodrug approach. Prodrugs are enzymatically or chemically transformed in vivo to produce active drugs. Among these, medoxomil promoieties have been judiciously employed in multiple drug discovery campaigns, leading to three prodrugs gaining FDA approval: azilsartan medoxomil (6), olmesartan medoxomil (20), and ceftobiprole medocaril (29), and one approval in Japan: prulifloxacin (35). The promoiety can be easily appended to mask carboxylic acids, amines, zwitterionic compounds, and other polar groups, imparting lipophilicity to the parent compound. The promoiety has the added advantage of rapid and complete conversion to the parent drug by multiple enzymatic pathways across different tissues. The approach has been used for drugs spanning multiple classes to improve oral bioavailability, solubility, tissue localization, efflux, and side effect profiles. This Perspective analyzes the history and application of medoxomil prodrugs and discusses their potential for drug development.