title: (±) cis-Bisamido epoxides: A novel series of potent FXIII-A inhibitors.
abstract: A novel class of potent FXIII-A inhibitors containing a (±) cis-bisamido epoxide pharmacophore is described. The compounds display highly potent inhibition of FXIII-A (IC50 = 5-500 nM) in an in vitro assay. In contrast to other types of previously described covalent transglutaminase inhibitors, the bis-amido epoxides exhibited no measurable reactivity with glutathione, therefore possibly rendering this class of compounds suitable for future in vivo investigations. Additionally, the compounds show selective inhibition for FXIII-A against the cysteine protease, cathepsin S although they proved to have similar potency with a closely related transglutaminase, TGII, to that observed for FXIII-A.
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Avery
authors.affiliation: Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Pease
authors.affiliation: Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Kerrie
authors.initials: K
authors.lastname: Smith
authors.affiliation: Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: May
authors.initials: M
authors.lastname: Boothby
authors.affiliation: Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Buckley
authors.affiliation: Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Grant
authors.affiliation: School of Chemistry, University of Leeds, Leeds LS2 9JT, UK. Electronic address: C.W.G.Fishwick@leeds.ac.uk.
authors.forename: Colin W G
authors.initials: CW
authors.lastname: Fishwick
mesh_terms: D004353:Drug Evaluation, Preclinical; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology*; D005176:Factor XIII / Q000037:antagonists & inhibitors*; D008958:Models, Molecular
chemical_list: D004852:Epoxy Compounds; D005176:Factor XIII
keywords: Bis-amido epoxides molecular modelling; FXIII-A; Thrombosis