Seite - (000219) - in Biomedical Chemistry: Current Trends and Developments

Figure 3.1.5: Structures of dapsone (R=H) and prodrugs with amino acids. Amino acid prodrugs are expected to pose synthetic challenges similar to other prodrugs. Amino acid prodrug linkage chemistry is well- established, therefore many of the synthetic challenges will depend on the number and type of protecting groups required to mask the active groups on the amino acid and parent drug. Furthermore, all amino acids except glycine introduce a stereocenter to the prodrug. Like other prodrugs, amino acid prodrugs increase the molecular weight of the parent, requiring mindfulness of the increase in dose due to the “non- active” contribution of the prodrug relative to the bioavailability enhancement with prodrug (Vig, 2013). 3.1.2.2 Amino Acid Prodrug in Drug Delivery Many drugs suffer from an extensive first-pass metabolism leading to drug inactivation and/or production of toxic metabolites, which makes them attractive targets for prodrug design. The classical prodrug approach, which involves enzyme-sensitive covalent linkage between the parent drug and a carrier moiety, is a well-established strategy to overcome bioavailability/toxicity issues. However, the development of prodrugs that can regenerate the parent drug through non-enzymatic pathways has emerged as an alternative approach in which prodrug activation is not influenced by inter- and intra-individual variability that affects enzymatic activity. As discussed above, amino acids are excellent promoieties to increase the aqueous solubility of the parent drug. To increase the dissolution rate further, amino acid prodrugs can be converted to their salt forms. In the following sections, we will present some examples of commercial as well as investigational amino acid prodrugs that have been designed to improve 1) oral bioavailability, 2) sustained drug delivery, 3) intravenous drug delivery, 4) to target drugs to their site of action and 5) improve enzymatic stability.