Iminosugars: Potential inhibitors of liver glycogen phosphorylase

Citation
P. Jakobsen et al., Iminosugars: Potential inhibitors of liver glycogen phosphorylase, BIO MED CH, 9(3), 2001, pp. 733-744
Citations number
25
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN journal
09680896 → ACNP
Volume
9
Issue
3
Year of publication
2001
Pages
733 - 744
Database
ISI
SICI code
0968-0896(200103)9:3<733:IPIOLG>2.0.ZU;2-L
Abstract
The first synthesis of the single isomers (3R,4R,5R); (3S,4S,5S); (3R,4R,5S ) and (3S,4S,5R) of 5-hydroxymethyl-piperidine-3,4-diol from Arecolin is re ported, including the synthesis of a series of N-substituted derivatives of the (3R,4R,5R)-isomer (Isofagomine). The inhibitory effect of these isomer s as well as of a series of N-substituted derivatives of the (3R,4R,SR)-iso mer and selected hydroxypiperidine analogues on liver glycogen phosphorylas e (GP) showed that the (3R,4R,5R) configuration was essential for obtaining an inhibitory effect at submicromolar concentration. The results also show ed that all three hydroxy groups should be present and could not be substit uted, nor were extra OH groups allowed if sub-micromolar inhibition should be obtained. Some inhibitory effect was retained for N-substituted derivati ves of Isofagagomine; however, N-substitution always resulted in a loss of activity compared to the parent compound, IC50 values ranging from 1 to 100 muM were obtained for simple alkyl, arylalkyl and benzoylmethyl substituen ts. Furthermore, we found that it was not enough to assure inhibitory effec t to have the (R,,R) configuration. Fagomine, the (2R,3R,4R)-2-hydroxymethy lpiperidine-3,4-diol analogue, showed an IC50 value of 200 muM compared to 0.7 muM for Isofagomine. In addition, Isofagomine was able to prevent basal and glucagon stimulated glycogen degradation in cultured hepatocytes with IC50 values of 2-3 muM. (C) 2001 Elsevier Science Ltd. All rights reserved.