Design and synthesis of 2-acetamidomethyl derivatives of isofagomine as potential inhibitors of human lysosomal beta-hexosaminidases.
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.
Leiden Institute of Chemistry, Gorlaeus Laboratories, University of Leiden, PO Box 9502, Leiden NL-2300 RA, The Netherlands.
Richard J B H N
RJ
van den Berg
Wilma
W
Donker-Koopman
Jacques H
JH
van Boom
Hans M F G
HM
Aerts
Daan
D
Noort
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005733:Gangliosidoses / Q000188:drug therapy; D006801:Humans; D050112:Imino Pyranoses; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008247:Lysosomes / Q000201:enzymology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013154:Spleen / Q000201:enzymology / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D050112:Imino Pyranoses; D010880:Piperidines; C098432:isofagomine; D001619:beta-N-Acetylhexosaminidases