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

Bioorg Med Chem Lett 2010 Aug 13;20(15):4715-8. Epub 2010 Apr 13.

Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.

Pyrrolo[2,3-f]isoquinoline based amino acids, tetracyclic lactams and cyclic ketone analogues are described as novel MK2 inhibitors with IC(50) as low as 5nM and good selectivity profiles against a number of related kinases including ERK, p38alpha and JNKs. TNFalpha release was suppressed from human peripheral blood mononuclear cells (hPBMCs), and a representative compound inhibited LPS induced TNFalpha release in mice illustrating the potential of this series to provide orally active MK2 inhibitors.

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http://dx.doi.org/10.1016/j.bmcl.2010.04.024DOI Listing
August 2010

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