BRUSH-BORDER-ENZYME-MEDIATED INTESTINE-SPECIFIC DRUG-DELIVERY - AMINO-ACID PRODRUGS OF 5-AMINOSALICYLIC ACID

5-Aminosalicylic acid (5-ASA) is the active principle of a number of p reparations aimed at the treatment of inflammatory bowel diseases, suc h as Crohn's disease and ulcerative colitis, but its efficacy is limit ed by early absorption and metabolism. The possibility to exploit the selective hydrolytic activity of brush border enzymes such as aminopep tidase A and carboxypeptidases was studied by preparing the following four amino acid prodrugs of 5-ASA: 5-(N-L-aspartylamino)-2-salicylic a cid, disodium salt (18), 5-(N-L-glutamylamino)-2-salicylic acid, disod ium salt (19), [(5-aminosalicyl)-L-prolyl]-L-leucine, sodium salt (25) , and 5-(N-L-glutamylamino)salicyl]-L-prolyl]-L-leucine, disodium salt (28). In these compounds, the peptide bond is selectively split by th e intestinal brush border aminopeptidase A (compounds 18, 19, and 28) and carboxypeptidases (compounds 25 and 28).