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Novel Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa) from Natural Product Anabaenopeptin

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journal contribution
posted on 11.06.2015, 00:00 by Nis Halland, Mark Brönstrup, Jörg Czech, Werngard Czechtizky, Andreas Evers, Markus Follmann, Markus Kohlmann, Matthias Schiell, Michael Kurz, Herman A. Schreuder, Christopher Kallus
Anabaenopeptins isolated from cyanobacteria were identified as inhibitors of carboxypeptidase TAFIa. Cocrystal structures of these macrocyclic natural product inhibitors in a modified porcine carboxypeptidase B revealed their binding mode and provided the basis for the rational design of small molecule inhibitors with a previously unknown central urea motif. Optimization based on these design concepts allowed for a rapid evaluation of the SAR and delivered potent small molecule inhibitors of TAFIa with a promising overall profile.