Novel Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa) from Natural Product Anabaenopeptin
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- 作者：Nis Halland ; Mark Br枚nstrup ; J枚rg Czech ; Werngard Czechtizky ; Andreas Evers ; Markus Follmann ; Markus Kohlmann ; Matthias Schiell ; Michael Kurz ; Herman A. Schreuder ; Christopher Kallus
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：June 11, 2015
- 年：2015
- 卷：58
- 期：11
- 页码：4839-4844
- 全文大小：382K
- ISSN：1520-4804
文摘
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.