Synthesis of C-5a-chain extended derivatives of 4-epi-isofagomine: Powerful β-galactosidase inhibitors and low concentration activators of GM1-gangliosidosis-related human lysosomal β-galactosidase

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 5; pp. 1438 - 1442
• Main Authors: Thonhofer, Martin, Weber, Patrick, Santana, Andres Gonzalez, Fischer, Roland, Pabst, Bettina M., Paschke, Eduard, Schalli, Michael, Stütz, Arnold E., Tschernutter, Marion, Windischhofer, Werner, Withers, Stephen G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2016
• Subjects: 4-epi-Isofagomine; beta-Galactosidase - antagonists & inhibitors; beta-Galactosidase - metabolism; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Galactosidase inhibitor; Gangliosidosis, GM1 - enzymology; Gangliosidosis, GM1 - pathology; GM1-gangliosidosis; Humans; Imino Pyranoses - chemical synthesis; Imino Pyranoses - chemistry; Imino Pyranoses - pharmacology; Iminoalditol; Lysosomes - drug effects; Lysosomes - enzymology; Models, Molecular; Molecular Structure; Pharmacological chaperone; Structure-Activity Relationship; Galactosidase inhibitor; GM1-gangliosidosis; Pharmacological chaperone; 4-epi-Isofagomine; Iminoalditol; G(M1)-gangliosidosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.01.059

[Display omitted] From an easily available partially protected formal derivative of 1-deoxymannojirimycin, by hydroxymethyl chain-branching and further elaboration, lipophilic analogs of the powerful β-d-galactosidase inhibitor 4-epi-isofagomine have become available. New compounds exhibit improved inhibitory activities comparable to benchmark compound NOEV (N-octyl-epi-valienamine) and may serve as leads towards improved and more selective pharmacological chaperones for GM1-gangliosidosis.