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

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 15, 2010, Pages 4719-4723

  Revesz, Laszlo ^a   Schlapbach, Achim ^a   Aichholz, Reiner ^a   Dawson, Janet ^a   Feifel, Roland ^a   Hawtin, Stuart ^a   Littlewood Evans, Amanda ^a   Koch, Guido ^a   Kroemer, Markus ^a   Möbitz, Henrik ^a   Scheufler, Clemens ^a   Velcicky, Juraj ^a   Huppertz, Christine ^a  

^a NOVARTIS PHARMA AG   (Switzerland)

Author keywords

Antiinflammatory; In vivo; Inhibition; MAPKAP K2; MK2; Rheumatoid arthritis; TNF

Indexed keywords

ANISOMYCIN; DEXAMETHASONE; ENZYME INHIBITOR; HEAT SHOCK PROTEIN 27; SPIROAZETIDINE; SPIROCYCLOPROPANE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ABSORPTION; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; HISTOLOGY; IC 50; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PROTEIN PHOSPHORYLATION; RAT; RHEUMATOID ARTHRITIS; SWELLING;

ADMINISTRATION, ORAL; ANIMALS; AZETIDINECARBOXYLIC ACID; AZETIDINES; BINDING SITES; CELL LINE; CRYSTALLOGRAPHY, X-RAY; CYCLOPROPANES; HSP27 HEAT-SHOCK PROTEINS; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MICE; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; SPIRO COMPOUNDS; STRUCTURE-ACTIVITY RELATIONSHIP; TUMOR NECROSIS FACTOR-ALPHA;

EID: 77955421113     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.04.023     Document Type: Article

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22. The X-ray coordinates are deposited with RCSB Protein Data Bank, deposition code is 3M2W. The protein used in this study is a segment of MK2 containing residues 47-364δ(216-237)G.
23. MK2-inhibitors (100 mg/kg p.o.) were administered to OFI mice (female, 8 weeks old), followed by LPS injection (20 mg/kg) 1 h later. One hour post LPS injection the experiment was terminated and blood withdrawn. Compound blood levels were determined by LC-MS/MS and plasma levels of mouse TNFα determined by ELISA.
24. Mouse CIA: Male DBA/1 mice (Janvier 10-12 weeks of age, were immunized with bovine collagen type II in CFA intradermally at the base of the tail. A second injection of bovime collagen type II in PBS was given ip on day 21. Upon initiation of swelling, mice were randomized into groups of 8 (test substance and vehicle) or 5 (steroid positive control) and treated with 13E, vehicle or dexamethasone from day 28 to day 41.
25. Rat AIA: Arthritis was induced in the right knee of rats by intra-articular injection of methylated bovine serum albumin (mBSA), in animals previously sensitised to the same antigen. Treatment was started orally on day 0, the day of arthritis induction, and continued for 7 days. Knee swelling was measured using digital calipers and expressed as a ratio of right (arthritic) vs left (control) knee swelling. The area under the curves (AUCs) of the treatment groups were then calculated as percentage inhibitions of the control vehicle treated animals.
26. Compound 13E was tested against a panel of 262 kinases at 1 μM and inhibited 14 human kinases with ≥95%: CaMKIIβ,χ,δ; CK1χ2,3; DAPK1,2; Met; Mnk2; PDGFRα(D842V); Pim-1; PRAK; ULK2; ZIPK.