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