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J Med Chem. 2015 Jun 11;58(11):4839-44. doi: 10.1021/jm501840b. Epub 2015 May 20.

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

Author information

1
‡Helmholtz Institute for Infection Research, Inhoffenstraße 7, D-38124 Braunschweig, Germany.
2
§Bayer Healthcare, Aprather Weg 18A, D-42113 Wuppertal, Germany.

Abstract

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.

PMID:
25990761
DOI:
10.1021/jm501840b
[Indexed for MEDLINE]

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