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The synthesis and SAR of tetracyclic MK2 inhibitors is reported. Spirocyclopropyl- and spiroazetidine groups attached to the δ-ring produced potent MK2-inhibitors with oral activity in the acute LPS-induced TNFα release model in mice. Compound 13E showed significant reduction of swelling and histological scores in two chronic arthritis models upon oral administration.
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<0.3μM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC50=0.05–0.23μM), less potent in cells (IC50<1.1μM), 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.