Design, synthesis, and biological evaluation of novel disubstituted dibenzosuberones as highly potent and selective inhibitors of p38 mitogen activated protein kinase.

Abstract:

:Synthesis, biological testing, structure-activity relationships (SARs), and selectivity of novel disubstituted dibenzosuberone derivatives as p38 MAP kinase inhibitors are described. Hydrophilic moieties were introduced at the 7-, 8-, and 9-position of the 2-phenylamino-dibenzosuberones, improving physicochemical properties as well as potency. Extremely potent inhibitors were obtained, with half-maximal inhibitory concentration (IC(50)) values in the low nM range in a whole blood assay measuring the inhibition of cytokine release. The high potency of the target compounds together with the outstanding selectivity of this novel class of compounds toward p38 mitogen activated protein (MAP) kinase as compared to other kinases indicate them to be most applicable as tools in pharmacological research and eventually they may foster a new generation of anti-inflammatory drugs.

journal_name

J Med Chem

authors

Koeberle SC,Fischer S,Schollmeyer D,Schattel V,Grütter C,Rauh D,Laufer SA

doi

10.1021/jm300327h

subject

Has Abstract

pub_date

2012-06-28 00:00:00

pages

5868-77

issue

12

eissn

0022-2623

issn

1520-4804

journal_volume

55

pub_type

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