Synthesis of C-5a-chain extended derivatives of 4-epi-isofagomine: Powerful beta-galactosidase inhibitors and low concentration activators of G(M1)-gangliosidosis-related human lysosomal beta-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, Stuetz, Arnold E., Tschernutter, Marion, Windischhofer, Werner, Withers, Stephen G.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 01.03.2016
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; 1-N-IMINOSUGARS; PHARMACOLOGICAL CHAPERONES; G(M1)-gangliosidosis; FLUOROUS IMINOALDITOLS; Pharmacological chaperone; 4-epi-Isofagomine; PATHOPHYSIOLOGY; Galactosidase inhibitor; POTENT; GLUCOCEREBROSIDASE; GLYCOSIDASE INHIBITOR; GM1 GANGLIOSIDOSIS; Iminoalditol; 1-DEOXYGALACTONOJIRIMYCIN; CHEMICAL CHAPERONE THERAPY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.01.059

From an easily available partially protected formal derivative of 1-deoxymannojirimycin, by hydroxymethyl chain-branching and further elaboration, lipophilic analogs of the powerful beta-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 G(M1)-gangliosidosis. (C) 2016 Elsevier Ltd. All rights reserved.