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