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

• Published in: Bioorganic & medicinal chemistry 2004-03, Vol.12 (5), p.891-902
• Main Authors: VAN DEN BERG, Richard J. B. H. N, DONKER-KOOPMAN, Wilma, VAN BOOM, Jacques H, AERTS, Hans M. F. G, NOORT, Daan
• Format: Article
• Language: English
• Subjects: beta-N-Acetylhexosaminidases - antagonists & inhibitors; Biological and medical sciences; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Gangliosidoses - drug therapy; General and cellular metabolism. Vitamins; Humans; Imino Pyranoses; Inhibitory Concentration 50; Kinetics; Lysosomes - enzymology; Medical sciences; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - pharmacology; Spleen - enzymology; Spleen - ultrastructure; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2003.12.040

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.