In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part II.
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Revesz L, Schlapbach A, Aichholz R, Dawson J, Feifel R, Hawtin S, Littlewood-Evans A, Koch G, Kroemer M, Mobitz H, Scheufler C, Velcicky J, Huppertz C
In vivo and in vitro SAR of tetracyclic MAPKAP-K2 (MK2) inhibitors. Part II.
Bioorg Med Chem Lett. 2010 Aug 1;20(15):4719-23. doi: 10.1016/j.bmcl.2010.04.023. Epub 2010 Apr 11.
- PubMed ID
- 20591669 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) 2-[2-(2-FLUOROPHENYL)PYRIDIN-4-YL]-1,5,6,7-TETRAHYDRO-4H-PYRROLO[3,2-C]PYRIDIN-4-ONE MAP kinase-activated protein kinase 2 IC 50 (nM) 560 N/A N/A Details 2-[2-(2-FLUOROPHENYL)PYRIDIN-4-YL]-1,5,6,7-TETRAHYDRO-4H-PYRROLO[3,2-C]PYRIDIN-4-ONE MAP kinase-activated protein kinase 2 IC 50 (nM) 8900 N/A N/A Details