Analogues of the pan-selectin antagonist rivipansel (GMI-1070).

Autor: Wagner B; University of Basel, Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Klingelbergstrasse 50, 4056, Basel, Switzerland., Smieško M; University of Basel, Department of Pharmaceutical Sciences, Group Computational Pharmacy, Klingelbergstrasse 50, 4056, Basel, Switzerland., Jakob RP; University of Basel, Department Biozentrum, Structural Area Focal Biology, Spitalstrasse 41, 4056, Basel, Switzerland., Mühlethaler T; University of Basel, Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Klingelbergstrasse 50, 4056, Basel, Switzerland., Cramer J; Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225, Düsseldorf, Germany., Maier T; University of Basel, Department Biozentrum, Structural Area Focal Biology, Spitalstrasse 41, 4056, Basel, Switzerland., Rabbani S; University of Basel, Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Klingelbergstrasse 50, 4056, Basel, Switzerland., Schwardt O; University of Basel, Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Klingelbergstrasse 50, 4056, Basel, Switzerland., Ernst B; University of Basel, Department of Pharmaceutical Sciences, Group Molecular Pharmacy, Klingelbergstrasse 50, 4056, Basel, Switzerland. Electronic address: beat.ernst@unibas.ch.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Jun 05; Vol. 272, pp. 116455. Date of Electronic Publication: 2024 Apr 30.
DOI: 10.1016/j.ejmech.2024.116455
Abstrakt: The selectin family consisting of E-, P- and L-selectin plays dominant roles in atherosclerosis, ischemia-reperfusion injury, inflammatory diseases, and metastatic spreading of some cancers. An early goal in selectin-targeted drug discovery campaigns was to identify ligands binding to all three selectins, so-called pan-selectin antagonists. The physiological epitope, tetrasaccharide sialyl Lewis x (sLe x , 1) binds to all selectins, albeit with very different affinities. Whereas P- and L-selectin require additional interactions contributed by sulfate groups for high binding affinity, E-selectin can functionally bind sLe x -modified glycolipids and glycoproteins. Rivipansel (3) marked the first pan-selectin antagonist, which simultaneously interacted with both the sLe x and the sulfate binding site. The aim of this contribution was to improve the pan-selectin affinity of rivipansel (3) by leveraging a new class of sLe x mimetics in combination with an optimized linker length to the sulfate bearing group. As a result, the pan-selectin antagonist 11b exhibits an approximatively 5-fold improved affinity for E-, as well as P-selectin.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Beat Ernst reports financial support was provided by GlycoMimetics Inc. Gaithersburg, Maryland 20,878, USA. Beat Ernst reports a relationship with GlycoMimetics Inc that includes:Funding grants. Beat Ernst has patent Heterobifuncional pan-selectin antagonists having a triazole linker issued to GlycoMimetics Inc. None If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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