Design and synthesis of 2-acetamidomethyl derivatives of isofagomine as potential inhibitors of human lysosomal beta-hexosaminidases.

Abstract

As part of a program towards the development of specific inhibitors of human lysosomal beta-hexosaminidase for use as chemical chaperones in therapy of G(M2) gangliosidosis related diseases, the synthesis of 2-acetamidomethyl derivatives of isofagomine has been undertaken. Key event in this synthesis is the conversion of a C-2 substituted gluconolactone derivative into the corresponding lactam, followed by reduction to the corresponding amine. The 1-N-imino-2 acetamidomethyl derivative 5 proved to be a rather selective inhibitor with a K(i) of 2.4 microM for homogenate of human spleen lysosomal beta-hexosaminidase.

• Authors: Richard J B H N van den Berg, Wilma Donker-Koopman, Jacques H van Boom, Hans M F G Aerts, Daan Noort
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 12 Issue 5 Pg. 891-902 (Mar 01 2004) ISSN: 0968-0896 [Print] England
• PMID: 14980601 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Imino Pyranoses
• Piperidines
• isofagomine
• beta-N-Acetylhexosaminidases

Topics

• Drug Design
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• Gangliosidoses (drug therapy)
• Humans
• Imino Pyranoses
• Inhibitory Concentration 50
• Kinetics
• Lysosomes (enzymology)
• Piperidines (chemical synthesis, pharmacology)
• Spleen (enzymology, ultrastructure)
• Structure-Activity Relationship
• beta-N-Acetylhexosaminidases (antagonists & inhibitors)