Page - (000299) - in Biomedical Chemistry: Current Trends and Developments

pharmacological effect. High PPB also reduces the clearance of a compound and thus increases the PK half-life, since it prevents the drug from permeating into the liver and kidneys (Kerns, 2008). A further dimension that must be considered when working with central nervous system (CNS) active agents is the uptake in the brain. Here, the blood–brain barrier (BBB) constitutes an additional barrier to absorption. It has been shown that the penetration of a compound into the brain decreases with increasing polar surface area (Van de Waterbeemd, 1998). However, it is not only the physiochemical properties that influence brain uptake. Transporters, especially PgP, and metabolizing enzymes are also limiting factors. Several structure modification strategies to reduce PgP efflux have been described (Kerns, 2008). These include reducing the number of hydrogen bond donors, decreasing the hydrogen bond acceptor potential of a compound, and decreasing the overall lipophilicity of the structure. During rational peptide lead optimization various in vitro property assays (e.g. solubility, permeability, chemical stability, metabolism, protein binding and transport) are used to assess the drug-like properties of the generated peptide analogues (Kerns, 2008). Extensive in vitro profiling regarding the PK data of lead compounds in the early stages of development can thus provide the medicinal chemist with information on the structure-property relationship important for the further development of orally active compounds. 3.3.1.1.2 Structure–Activity Relationship In order to develop peptidomimetics with retained affinity to the biological target it is crucial to investigate what parts of the peptide are directly involved in target recognition. Thus, attainment of the structure–activity relationships (SARs) and identification of the minimal active sequence of the peptide required for biological activity are important first steps in the process. This is normally achieved by the evaluation of binding affinities of peptide analogs to the target protein. In practice, such information is normally gathered through amino acid scans, truncations and N- and C-terminal modifications (Grauer, 2009; Hruby, 2002; Wiley, 1993; Vlieghe, 2010). Amino acid scans determine