(±) cis-bisamido epoxides: A novel series of potent FXIII-A inhibitors

Craig A. Avery; Richard J. Pease; Kerrie Smith; May Boothby; Helen M. Buckley; Peter J. Grant; Colin W.G. Fishwick

doi:10.1016/j.ejmech.2015.05.019

(±) cis-bisamido epoxides: A novel series of potent FXIII-A inhibitors

Craig A. Avery, Richard J. Pease, Kerrie Smith, May Boothby, Helen M. Buckley, Peter J. Grant, Colin W.G. Fishwick

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

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 Combining double low line 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.

Original language	English
Pages (from-to)	49-53
Number of pages	5
Journal	European Journal of Medicinal Chemistry
Volume	98
DOIs	https://doi.org/10.1016/j.ejmech.2015.05.019
Publication status	Published - 26 May 2015
Externally published	Yes

Keywords

Bis-Amido epoxides molecular modelling
FXIII-A
Thrombosis

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10.1016/j.ejmech.2015.05.019

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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 Combining double low line 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.",

keywords = "Bis-Amido epoxides molecular modelling, FXIII-A, Thrombosis",

author = "Avery, {Craig A.} and Pease, {Richard J.} and Kerrie Smith and May Boothby and Buckley, {Helen M.} and Grant, {Peter J.} and Fishwick, {Colin W.G.}",

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year = "2015",

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doi = "10.1016/j.ejmech.2015.05.019",

language = "English",

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TY - JOUR

T1 - (±) cis-bisamido epoxides

T2 - A novel series of potent FXIII-A inhibitors

AU - Avery, Craig A.

AU - Pease, Richard J.

AU - Smith, Kerrie

AU - Boothby, May

AU - Buckley, Helen M.

AU - Grant, Peter J.

AU - Fishwick, Colin W.G.

PY - 2015/5/26

Y1 - 2015/5/26

N2 - 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 Combining double low line 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.

AB - 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 Combining double low line 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.

KW - Bis-Amido epoxides molecular modelling

KW - FXIII-A

KW - Thrombosis

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U2 - 10.1016/j.ejmech.2015.05.019

DO - 10.1016/j.ejmech.2015.05.019

M3 - Article

C2 - 26005023

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SN - 0223-5234

VL - 98

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EP - 53

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

(±) cis-bisamido epoxides: A novel series of potent FXIII-A inhibitors

Abstract

Keywords

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