title: Novel Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa) from Natural Product Anabaenopeptin.
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.
authors.forename: Nis
authors.initials: N
authors.lastname: Halland
authors.affiliation: ‡Helmholtz Institute for Infection Research, Inhoffenstraße 7, D-38124 Braunschweig, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Brönstrup
authors.forename: Jörg
authors.initials: J
authors.lastname: Czech
authors.forename: Werngard
authors.initials: W
authors.lastname: Czechtizky
authors.forename: Andreas
authors.initials: A
authors.lastname: Evers
authors.affiliation: §Bayer Healthcare, Aprather Weg 18A, D-42113 Wuppertal, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Follmann
authors.forename: Markus
authors.initials: M
authors.lastname: Kohlmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Schiell
authors.forename: Michael
authors.initials: M
authors.lastname: Kurz
authors.forename: Herman A
authors.initials: HA
authors.lastname: Schreuder
authors.forename: Christopher
authors.initials: C
authors.lastname: Kallus
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D000458:Cyanobacteria / Q000737:chemistry; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D001688:Biological Products; D010456:Peptides, Cyclic; D054852:Small Molecule Libraries; D025901:Carboxypeptidase B2