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In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part I.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2010 Aug 01; Vol. 20 (15), pp. 4715-8. Date of Electronic Publication: 2010 Apr 13. - Publication Year :
- 2010
-
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.<br /> (Copyright 2010 Elsevier Ltd. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 20
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 20594847
- Full Text :
- https://doi.org/10.1016/j.bmcl.2010.04.024