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

…, R Feifel, S Hawtin, A Littlewood-Evans, G Koch…

Index: Revesz, Laszlo; Schlapbach, Achim; Aichholz, Reiner; Dawson, Janet; Feifel, Roland; Hawtin, Stuart; Littlewood-Evans, Amanda; Koch, Guido; Kroemer, Markus; Moebitz, Henrik; Scheufler, Clemens; Velcicky, Juraj; Huppertz, Christine Bioorganic and Medicinal Chemistry Letters, 2010 , vol. 20, # 15 p. 4719 - 4723

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Citation Number: 21

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 IC50< 3nM and inhibit the release of TNFα (IC50< 0.3 μM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC50= 0.05–0.23 μM), less potent in cells (IC50< 1.1 μM), but ...