Structure-Activity Relationship Studies of Emtricitabine Prodrugs toward Long-Acting Antiretroviral Formulations.

Long-acting injectable (LAI) antiretroviral (ARV) approaches are needed to address poor adherence to oral drug regimens in the treatment and prevention of human immunodeficiency virus (HIV). We have previously reported semisolid prodrug nanoparticle (SSPN) LAI formulations of emtricitabine (FTC) that showed extended pharmacokinetic half-lives in vivo. Here, we report the design, synthesis, and evaluation of FTC octyl carbamate prodrugs masked with a variety of bioreversible protecting groups at the 5'-position. We show that 5'-modifications displaying a range of hydrolytic stabilities in biomatrices are compatible with the LAI formulation by the emulsion-templated freeze-drying (ETFD) method. The results demonstrate the feasibility of tuning prodrug activation kinetics while maintaining LAI compatibility, which is critical for the development of nucleoside reverse transcriptase inhibitor (NRTI)-containing LAI-ARV therapies.