title: Sulfamide as Zinc Binding Motif in Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa).
abstract: Previously disclosed TAFIa inhibitors having a urea zinc-binding motif were used as the starting point for the development of a novel class of highly potent inhibitors having a sulfamide zinc-binding motif. High-resolution X-ray cocrystal structures were used to optimize the structures and reveal a highly unusual sulfamide configuration. A selected sulfamide was profiled in vitro and in vivo and displayed a promising ADMET profile.
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Nis
authors.initials: N
authors.lastname: Halland
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Czech
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Werngard
authors.initials: W
authors.lastname: Czechtizky
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Evers
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Follmann
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kohlmann
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Herman A
authors.initials: HA
authors.lastname: Schreuder
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kallus
mesh_terms: D000818:Animals; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D015032:Zinc / Q000737:chemistry*
chemical_list: D011480:Protease Inhibitors; D054852:Small Molecule Libraries; D013449:Sulfonamides; D025901:Carboxypeptidase B2; D015032:Zinc