Seite - (000318) - in Biomedical Chemistry: Current Trends and Developments

Figure 3.3.11: Overview of different modification strategies. 3.3.2.3.2 Structure–activity relationship and ADME properties The binding affinities of the dipeptides were evaluated as described previously. The dipeptide lead H-Phe-Phe-NH2 was re-tested with the new peptides for a more accurate comparison of the Ki values. The metabolic stability was evaluated by incubating the peptides with pooled human liver microsomes. In vitro half-life (t1/2) and in vitro intrinsic clearance (Clint) were calculated using previously reported models (Houston, 1994; Obach, 1999). The Ki values and metabolic stabilities (t1/2 and Clint) of the methylated analogs 33–37 are presented in Table 3.3.5, while the results of the rigidified and C-terminal- phenylalanine-modified analogs 38–43 are presented in Table 3.3.6. Table 3.3.5: Binding affinity (Ki values) and metabolic stability (Clint and t1/2) of the methylated H-Phe-Phe-NH2 analogs