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Your search keyword '"Huppertz, Christine"' showing total 5 results
Start Over Author "Huppertz, Christine" Topic protein serine-threonine kinases
5 results on '"Huppertz, Christine"'

1. In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part II.

Author

Revesz L, Schlapbach A, Aichholz R, Dawson J, Feifel R, Hawtin S, Littlewood-Evans A, Koch G, Kroemer M, Möbitz H, Scheufler C, Velcicky J, and Huppertz C

Subjects
Administration, Oral, Animals, Azetidinecarboxylic Acid chemical synthesis, Azetidinecarboxylic Acid pharmacology, Azetidines chemistry, Binding Sites, Cell Line, Crystallography, X-Ray, Cyclopropanes chemistry, Cyclopropanes pharmacology, HSP27 Heat-Shock Proteins metabolism, Humans, Intracellular Signaling Peptides and Proteins metabolism, Mice, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases metabolism, Spiro Compounds chemistry, Structure-Activity Relationship, Tumor Necrosis Factor-alpha metabolism, Azetidinecarboxylic Acid chemistry, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases antagonists & inhibitors
Abstract

Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D-E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC(50)<3 nM and inhibit the release of TNFalpha (IC(50)<0.3 microM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC(50)=0.05-0.23 microM), less potent in cells (IC(50)<1.1 microM), but show good oral absorption. Compound 13E (100mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Published
2010
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2. In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part I.

Author

Revesz L, Schlapbach A, Aichholz R, Feifel R, Hawtin S, Heng R, Hiestand P, Jahnke W, Koch G, Kroemer M, Möbitz H, Scheufler C, Velcicky J, and Huppertz C

Subjects
Administration, Oral, Amino Acids chemical synthesis, Amino Acids chemistry, Amino Acids pharmacology, Animals, Binding Sites, Crystallography, X-Ray, Heterocyclic Compounds, 4 or More Rings chemical synthesis, Heterocyclic Compounds, 4 or More Rings pharmacology, Humans, Intracellular Signaling Peptides and Proteins metabolism, Isoquinolines chemistry, Ketones chemical synthesis, Ketones chemistry, Ketones pharmacology, Lactams chemical synthesis, Lactams chemistry, Lactams pharmacology, Mice, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases metabolism, Pyrroles chemistry, Structure-Activity Relationship, Tumor Necrosis Factor-alpha metabolism, Heterocyclic Compounds, 4 or More Rings chemistry, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases antagonists & inhibitors
Abstract

Pyrrolo[2,3-f]isoquinoline based amino acids, tetracyclic lactams and cyclic ketone analogues are described as novel MK2 inhibitors with IC(50) as low as 5nM and good selectivity profiles against a number of related kinases including ERK, p38alpha and JNKs. TNFalpha release was suppressed from human peripheral blood mononuclear cells (hPBMCs), and a representative compound inhibited LPS induced TNFalpha release in mice illustrating the potential of this series to provide orally active MK2 inhibitors., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Published
2010
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3. Novel 3-aminopyrazole inhibitors of MK-2 discovered by scaffold hopping strategy.

Author

Velcicky J, Feifel R, Hawtin S, Heng R, Huppertz C, Koch G, Kroemer M, Moebitz H, Revesz L, Scheufler C, and Schlapbach A

Subjects
Cell Line, Tumor, Cells, Cultured, Crystallography, X-Ray, Humans, Intracellular Signaling Peptides and Proteins metabolism, Protein Conformation, Protein Serine-Threonine Kinases metabolism, Pyrazoles metabolism, Pyrazoles pharmacology, Drug Discovery methods, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrazoles chemistry
Abstract

New, selective 3-aminopyrazole based MK2-inhibitors were discovered by scaffold hopping strategy. The new derivatives proved to inhibit intracellular phosphorylation of hsp27 as well as LPS-induced TNFalpha release in cells. In addition, selected derivative 14e also inhibited LPS-induced TNFalpha release in vivo., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Published
2010
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4. Low-molecular-weight MK2 inhibitors: a tough nut to crack!

Author

Schlapbach A and Huppertz C

Subjects
Adenosine Triphosphate analogs & derivatives, Adenosine Triphosphate pharmacology, Animals, Anti-Inflammatory Agents pharmacology, Intracellular Signaling Peptides and Proteins metabolism, Molecular Weight, Patents as Topic, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases metabolism, Rats, Tumor Necrosis Factor-alpha metabolism, Anti-Inflammatory Agents chemistry, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases antagonists & inhibitors
Abstract

The p38 pathway has been at the center of interest for anti-inflammatory drug discovery for many years as it is crucial for the biosynthesis of TNF-α, IL-1β and other mediators. Most of the anti-inflammatory effects of p38 inhibition are mediated through MAPK-activated protein kinase-2 (MK2), a direct downstream target of p38, which makes MK2 a very interesting drug target. Within the last 5 years, several classes of low-molecular-weight MK2 inhibitors were disclosed in the patent and primary literature. Advanced compounds could be optimized to nanomolar potencies and inhibit TNF-α release, as well as the phosphorylation of the MK2 substrate heat-shock protein 27 in cellular assays. This article will review the recent progress in this field and will highlight and discuss the most promising compound series disclosed so far.

Published
2009
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5. Pyrrolo-pyrimidones: a novel class of MK2 inhibitors with potent cellular activity.

Author

Schlapbach A, Feifel R, Hawtin S, Heng R, Koch G, Moebitz H, Revesz L, Scheufler C, Velcicky J, Waelchli R, and Huppertz C

Subjects
Arthritis, Rheumatoid drug therapy, Combinatorial Chemistry Techniques, Cytokines metabolism, Dose-Response Relationship, Drug, Drug Design, HSP27 Heat-Shock Proteins antagonists & inhibitors, HSP27 Heat-Shock Proteins metabolism, Humans, Leukocytes, Mononuclear drug effects, Lipopolysaccharides pharmacology, Molecular Structure, Monocytes drug effects, Phosphorylation, Pyrimidinones chemistry, Pyrroles chemistry, Tumor Necrosis Factor-alpha antagonists & inhibitors, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrimidinones chemical synthesis, Pyrimidinones pharmacology, Pyrroles chemical synthesis, Pyrroles pharmacology
Abstract

Pyrrolo-pyrimidones of the general structure 1 were synthesized and evaluated for their potential as MK2 inhibitors. Potent derivatives were discovered which inhibit MK2 in the nanomolar range and show potent inhibition of cytokine release from LPS-stimulated monocytes. These derivatives were shown to inhibit phosphorylation of hsp27, a downstream target of MK2 and are modestly selective in a panel of 28 kinases.

Published
2008
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