Syntheses and structure-activity relationships for some triazolyl p38 alpha MAPK inhibitors

Jean-Paul G. Seerden; Gabriela Leusink-Ionescu; Robin Leguijt; Catherine Saccavini; Edith Gelens; Bas Dros; Titia Woudenberg-Vrenken; Grietje Molema; Jan A. A. M. Kamps; Richard M. Kellogg

doi:10.1016/j.bmcl.2014.01.034

Syntheses and structure-activity relationships for some triazolyl p38 alpha MAPK inhibitors

Jean-Paul G. Seerden^*, Gabriela Leusink-Ionescu, Robin Leguijt, Catherine Saccavini, Edith Gelens, Bas Dros, Titia Woudenberg-Vrenken, Grietje Molema, Jan A. A. M. Kamps, Richard M. Kellogg

^*Corresponding author voor dit werk

Onderzoeksoutput: Article › Academic › peer review

19 Citaten (Scopus)

Samenvatting

The design, synthesis and biological evaluation of novel triazolyl p38 alpha MAPK inhibitors with improved water solubility for formulation in cationic liposomes (SAINT-O-Somes) targeted at diseased endothelial cells is described. Water-solubilizing groups were introduced via a 'click' reaction of functional azides with 2-alkynyl imidazoles and isosteric oxazoles to generate two small libraries of 1,4-disubstituted 1,2,3-triazolyl p38 alpha MAPK inhibitors. Triazoles with low IC50 values and desired physicochemical properties were screened for in vitro downregulation of proinflammatory gene expression and were formulated in SAINT-O-Somes. Triazolyl p38 alpha MAPK inhibitor 88 (IC50 = 0.096 mu M) displayed the most promising in vitro activity. (C) 2014 Elsevier Ltd. All rights reserved.

Originele taal-2	English
Pagina's (van-tot)	1352-1357
Aantal pagina's	6
Tijdschrift	Bioorganic & Medicinal Chemistry Letters
Volume	24
Nummer van het tijdschrift	5
DOI's	https://doi.org/10.1016/j.bmcl.2014.01.034
Status	Published - 1-mrt.-2014

Toegang tot document

10.1016/j.bmcl.2014.01.034

Handle.net

Permanente koppeling

Document onder embargo

Syntheses and structure-activity relationships for some triazolyl p38 alpha MAPK
Final publisher's version, 3,58 MB
Kopie aanvragen

Citeer dit

@article{40b71ab741644889aae494cedfc5b5b2,

title = "Syntheses and structure-activity relationships for some triazolyl p38 alpha MAPK inhibitors",

abstract = "The design, synthesis and biological evaluation of novel triazolyl p38 alpha MAPK inhibitors with improved water solubility for formulation in cationic liposomes (SAINT-O-Somes) targeted at diseased endothelial cells is described. Water-solubilizing groups were introduced via a 'click' reaction of functional azides with 2-alkynyl imidazoles and isosteric oxazoles to generate two small libraries of 1,4-disubstituted 1,2,3-triazolyl p38 alpha MAPK inhibitors. Triazoles with low IC50 values and desired physicochemical properties were screened for in vitro downregulation of proinflammatory gene expression and were formulated in SAINT-O-Somes. Triazolyl p38 alpha MAPK inhibitor 88 (IC50 = 0.096 mu M) displayed the most promising in vitro activity. (C) 2014 Elsevier Ltd. All rights reserved.",

keywords = "p38 alpha MAPK inhibitors, Triazole, COX-2, IL-6, Inflammation, KINASE INHIBITORS, CLICK CHEMISTRY, PHYSICOCHEMICAL PROPERTIES, DIRECT ALKYNYLATION, ENDOTHELIAL-CELLS, IN-VITRO, POTENT, IMIDAZOLE, DESIGN, CYCLOADDITION",

author = "Seerden, {Jean-Paul G.} and Gabriela Leusink-Ionescu and Robin Leguijt and Catherine Saccavini and Edith Gelens and Bas Dros and Titia Woudenberg-Vrenken and Grietje Molema and Kamps, {Jan A. A. M.} and Kellogg, {Richard M.}",

year = "2014",

month = mar,

day = "1",

doi = "10.1016/j.bmcl.2014.01.034",

language = "English",

volume = "24",

pages = "1352--1357",

journal = "Bioorganic & Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "American Chemical Society",

number = "5",

}

TY - JOUR

T1 - Syntheses and structure-activity relationships for some triazolyl p38 alpha MAPK inhibitors

AU - Seerden, Jean-Paul G.

AU - Leusink-Ionescu, Gabriela

AU - Leguijt, Robin

AU - Saccavini, Catherine

AU - Gelens, Edith

AU - Dros, Bas

AU - Woudenberg-Vrenken, Titia

AU - Molema, Grietje

AU - Kamps, Jan A. A. M.

AU - Kellogg, Richard M.

PY - 2014/3/1

Y1 - 2014/3/1

N2 - The design, synthesis and biological evaluation of novel triazolyl p38 alpha MAPK inhibitors with improved water solubility for formulation in cationic liposomes (SAINT-O-Somes) targeted at diseased endothelial cells is described. Water-solubilizing groups were introduced via a 'click' reaction of functional azides with 2-alkynyl imidazoles and isosteric oxazoles to generate two small libraries of 1,4-disubstituted 1,2,3-triazolyl p38 alpha MAPK inhibitors. Triazoles with low IC50 values and desired physicochemical properties were screened for in vitro downregulation of proinflammatory gene expression and were formulated in SAINT-O-Somes. Triazolyl p38 alpha MAPK inhibitor 88 (IC50 = 0.096 mu M) displayed the most promising in vitro activity. (C) 2014 Elsevier Ltd. All rights reserved.

AB - The design, synthesis and biological evaluation of novel triazolyl p38 alpha MAPK inhibitors with improved water solubility for formulation in cationic liposomes (SAINT-O-Somes) targeted at diseased endothelial cells is described. Water-solubilizing groups were introduced via a 'click' reaction of functional azides with 2-alkynyl imidazoles and isosteric oxazoles to generate two small libraries of 1,4-disubstituted 1,2,3-triazolyl p38 alpha MAPK inhibitors. Triazoles with low IC50 values and desired physicochemical properties were screened for in vitro downregulation of proinflammatory gene expression and were formulated in SAINT-O-Somes. Triazolyl p38 alpha MAPK inhibitor 88 (IC50 = 0.096 mu M) displayed the most promising in vitro activity. (C) 2014 Elsevier Ltd. All rights reserved.

KW - p38 alpha MAPK inhibitors

KW - Triazole

KW - COX-2, IL-6

KW - Inflammation

KW - KINASE INHIBITORS

KW - CLICK CHEMISTRY

KW - PHYSICOCHEMICAL PROPERTIES

KW - DIRECT ALKYNYLATION

KW - ENDOTHELIAL-CELLS

KW - IN-VITRO

KW - POTENT

KW - IMIDAZOLE

KW - DESIGN

KW - CYCLOADDITION

U2 - 10.1016/j.bmcl.2014.01.034

DO - 10.1016/j.bmcl.2014.01.034

M3 - Article

SN - 0960-894X

VL - 24

SP - 1352

EP - 1357

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

IS - 5

ER -

Syntheses and structure-activity relationships for some triazolyl p38 alpha MAPK inhibitors

Samenvatting

Toegang tot document

Handle.net

Document onder embargo

Vingerafdruk

Citeer dit