Brush-border-enzyme-mediated intestine-specific drug delivery. Amino acid prodrugs of 5-aminosalicylic acid

J Med Chem. 1993 Dec 24;36(26):4201-7. doi: 10.1021/jm00078a009.

Abstract

5-Aminosalicylic acid (5-ASA) is the active principle of a number of preparations aimed at the treatment of inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis, but its efficacy is limited by early absorption and metabolism. The possibility to exploit the selective hydrolytic activity of brush border enzymes such as aminopeptidase A and carboxypeptidases was studied by preparing the following four amino acid prodrugs of 5-ASA: 5-(N-L-aspartylamino)-2-salicylic acid, disodium salt (18), 5-(N-L-glutamylamino)-2-salicylic acid, disodium 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 the intestinal brush border aminopeptidase A (compounds 18, 19, and 28) and carboxypeptidases (compounds 25 and 28).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids*
  • Aminopeptidases / metabolism
  • Aminosalicylic Acids / pharmacokinetics*
  • Aminosalicylic Acids / urine
  • Animals
  • Carboxypeptidases / metabolism
  • Colon / metabolism
  • Colostomy
  • Feces
  • Glutamyl Aminopeptidase
  • Hydrolysis
  • Ileum / metabolism
  • Inflammatory Bowel Diseases / drug therapy
  • Intestinal Absorption*
  • Intestines / enzymology*
  • Kinetics
  • Male
  • Mesalamine
  • Microvilli / enzymology
  • Prodrugs / pharmacokinetics*
  • Rats

Substances

  • Amino Acids
  • Aminosalicylic Acids
  • Prodrugs
  • Mesalamine
  • Carboxypeptidases
  • Aminopeptidases
  • Glutamyl Aminopeptidase