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

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.
Laszlo Revesz 1,  Achim Schlapbach,  Reiner Aichholz,  Janet Dawson,  Roland Feifel,  Stuart Hawtin,  Amanda Littlewood-Evans,  Guido Koch,  Markus Kroemer,  Henrik Möbitz,  Clemens Scheufler,  Juraj Velcicky,  Christine Huppertz
Affiliations

Affiliation

  • 1 Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. laszlo.revesz@pharma.novartis.com
PMID: 20591669 DOI: 10.1016/j.bmcl.2010.04.023
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.

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