Page - (000317) - in Biomedical Chemistry: Current Trends and Developments

3.3.2.3.1 Strategy The potent dipeptide lead H-Phe-Phe-NH2 (26), discussed above, was chosen for further optimization studies with the overall aim of developing metabolically stable and selective SP1–7 analogs. The introduction of local constraints can enhance stability, selectivity and bioavailability. The intestinal permeability is an important factor in the development of orally bioavailable drugs. In the intestine, the di/tri- peptide transporter PepT1 enables the absorption of small peptides from the digestion of dietary proteins. This transport system has also been shown to transport a variety of peptidomimetic drugs, such as β-lactam antibiotics and ACE inhibitors and might be exploited in order to increase the absorption of our small compounds (Brandsch, 2009; Brodin, 2002; Rubio-Aliaga, 2002). A known problem with peptides is their susceptibility to efflux. For peptides targeting functions in the CNS, uptake in the brain, i.e. crossing the BBB, is a crucial factor. As a defense mechanism preventing harmful substances from entering the brain, the BBB is equipped with efflux transporters (Witt, 2001). PgP is one of the most important, and can actively transport substances out of the brain (Giacomini, 2010). Such transporters can be an obstacle to entering the CNS. A series of H-Phe-Phe-NH2 analogs (33–43, Tables 3.3.5 and 3.3.6) incorporating different types of constraints were designed, synthesized and evaluated regarding their binding affinity, stability, uptake and permeability (Fig. 3.3.11). N-methyl and α-methyl amino acids were incorporated, substituting one residue at a time. Furthermore, β- methylation of the phenylalanine side chain was used to reduce the conformational flexibility, which can be advantageous upon binding. This approach has been successful in other projects in obtaining neuropeptide analogs resistant to metabolism while still retaining their biological activity (Veber, 1985). Both N- and C-terminal rigidifications were accomplished by the introduction of a 3-phenylproline derivative (Sewald, 2002).