title: Rational design of novel, potent small molecule pan-selectin antagonists.
abstract: This report describes the first results of a rational hit-finding strategy to design novel small molecule antiinflammatory drugs targeting selectins, a family of three cellular adhesion molecules. Based on recent progress in understanding of molecular interaction between selectins and their natural ligands as well as progress in clinical development of synthetic antagonists like 1 (bimosiamose, TBC1269), this study was initiated to discover small molecule selectin antagonists with improved pharmacological properties. Considering 1 as template structure, a ligand-based approach followed by focused chemical synthesis has been applied to yield novel synthetic small molecules (MWr < 500) with a trihydroxybenzene motif, bearing neither peptidic nor glycosidic components, with nanomolar in vitro activity. Biological evaluation involves two kinds of in vitro assays, a static molecular binding assay, and a dynamic HL-60 cell attachment assay. As compared to controls, the novel compounds showed improved biological in vitro activity both under static and dynamic conditions.
authors.affiliation: Revotar Biopharmaceuticals AG, Neuendorfstrasse 24a, 16761 Hennigsdorf, Germany.
authors.forename: Remo
authors.initials: R
authors.lastname: Kranich
authors.forename: Anke S
authors.initials: AS
authors.lastname: Busemann
authors.forename: Daniel
authors.initials: D
authors.lastname: Bock
authors.forename: Sabine
authors.initials: S
authors.lastname: Schroeter-Maas
authors.forename: Diana
authors.initials: D
authors.lastname: Beyer
authors.forename: Bo
authors.initials: B
authors.lastname: Heinemann
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer
authors.forename: Katrin
authors.initials: K
authors.lastname: Schierhorn
authors.forename: Rainer
authors.initials: R
authors.lastname: Zahlten
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wolff
authors.forename: Ewald M
authors.initials: EM
authors.lastname: Aydt
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002448:Cell Adhesion; D015195:Drug Design; D019040:E-Selectin / Q000378:metabolism; D018922:HL-60 Cells; D006586:Hexanes / Q000737:chemistry*; D006801:Humans; D019041:L-Selectin / Q000378:metabolism; D008024:Ligands; D008358:Mannose / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D019007:P-Selectin / Q000378:metabolism; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D019087:Selectins / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019040:E-Selectin; D006586:Hexanes; D008024:Ligands; D019007:P-Selectin; D010636:Phenols; D019087:Selectins; D019041:L-Selectin; C496819:bimosiamose; D008358:Mannose