Bioavailability complex substrates

Complexation is one of several ways to favorably enhance the physicochemical properties of pharmaceutical compounds. It may loosely be defined as the reversible association of a substrate and ligand to form a new species. Although the classification of complexes is somewhat arbitrary, the differentiation is usually based on the types of interactions and species involved, e.g., metal complexes, molecular complexes, inclusion complexes, and ion-exchange compounds. Cyclodextrins (CDs) are classic examples of compounds that form inclusion complexes. These complexes are formed when a guest molecule is partially or fully included inside a host molecule e.g., CD with no covalent bonding. When inclusion complexes are formed, the physicochemical parameters of the guest molecule are disguised or altered and improvements in the molecule s solubility, stability, taste, safety, bioavailability, etc., are commonly seen. 

The discovery of peptide-based substrate-mimicking HIVPI was directed towards the synthesis of substrate analogs in which the scissile bond was replaced by a non-cleavable isostere with tetrahedral geometry that could mimic the tetrahedral transition-state of the proteolytic reaction. Thus, several inhibitors with hydroxyethylene or hydroxyethylamine isostere replacement were prepared to bind with the enzyme as shown in Fig. 3a [31]. However, the clinical development of peptide-derived compounds was hindered by their poor pharmacokinetics, including low oral bioavailability, rapid excretion and complex (expensive) synthesis [44,45]. Therefore, recently more... 

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