Design strategies in the prodrugs of HIV-1 protease inhibitors to improve the pharmaceutical properties

• Published in: European journal of medicinal chemistry 2017-10, Vol.139, p.865-883
• Main Authors: Subbaiah, Murugaiah A.M., Meanwell, Nicholas A., Kadow, John F.
• Format: Article
• Language: English
• Subjects: Dose-Response Relationship, Drug; Drug Design; HIV Infections - drug therapy; HIV Protease - metabolism; HIV-1; HIV-1 - metabolism; Metabolism; Molecular Structure; Oral bioavailability; Permeability; Prodrug; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Protease inhibitors; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Solubility; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.07.044

Combination antiretroviral therapy (cART) is currently the most effective treatment for HIV-1 infection. HIV-1 protease inhibitors (PIs) are an important component of some regimens of cART. However, PIs are known for sub-optimal ADME properties, resulting in poor oral bioavailability. This often necessitates high drug doses, combination with pharmacokinetic enhancers and/or special formulations in order to effectively deliver PIs, which may lead to a high pill burden and reduced patient compliance. As a remedy, improving the ADME properties of existing drugs via prodrug and other approaches has been pursued in addition to the development of next generation PIs with improved pharmacokinetic, resistance and side effect profiles. Phosphate prodrugs have been explored to address the solubility-limiting absorption and high excipient load. Prodrug design to target carrier-mediated drug delivery has also been explored. Amino acid prodrugs have been shown to improve permeability by engaging active transport mechanisms, reduce efflux and mitigate first pass metabolism while acyl migration prodrugs have been shown to improve solubility. Prodrug design efforts have led to the identification of one marketed agent, fosamprenavir, and clinical studies with two other prodrugs. Several of the reported approaches lack detailed in vivo characterization and hence the potential preclinical or clinical benefits of these approaches are yet to be fully determined. [Display omitted] •HIV-1 protease inhibitors (PIs) remain important therapeutics to treat HIV-1 infection.•Sub-optimal properties of PIs contribute to poor oral bioavailability and high pill burden.•There is a growing interest in prodrug-mediated drug delivery across therapeutic classes.•Phosphate, amino acid, acyl migration and other prodrugs of PIs have been explored with the discovery of fosamprenavir as the first marked prodrug example.•Challenges of prodrug discovery and future considerations in lead optimization are discussed.