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Rational design of novel, potent small molecule pan-selectin antagonists.
Kranich, Remo; Busemann, Anke S; Bock, Daniel; Schroeter-Maas, Sabine; Beyer, Diana; Heinemann, Bo; Meyer, Michael; Schierhorn, Katrin; Zahlten, Rainer; Wolff, Gerhard; Aydt, Ewald M.
Afiliação
  • Kranich R; Revotar Biopharmaceuticals AG, Neuendorfstrasse 24a, 16761 Hennigsdorf, Germany.
J Med Chem ; 50(6): 1101-15, 2007 Mar 22.
Article em En | MEDLINE | ID: mdl-17302397
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.
Assuntos
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Base de dados: MEDLINE Assunto principal: Fenóis / Anti-Inflamatórios não Esteroides / Selectinas / Hexanos / Manose Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2007 Tipo de documento: Article
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Base de dados: MEDLINE Assunto principal: Fenóis / Anti-Inflamatórios não Esteroides / Selectinas / Hexanos / Manose Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2007 Tipo de documento: Article