Development of N-2,4-pyrimidine-N-phenyl-N'-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-alpha) synthesis. Part 1.

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Brugel TA, Maier JA, Clark MP, Sabat M, Golebiowski A, Bookland RG, Laufersweiler MJ, Laughlin SK, Vanrens JC, De B, Hsieh LC, Mekel MJ, Janusz MJ

Development of N-2,4-pyrimidine-N-phenyl-N'-phenyl ureas as inhibitors of tumor necrosis factor alpha (TNF-alpha) synthesis. Part 1.

Bioorg Med Chem Lett. 2006 Jul 1;16(13):3510-3. Epub 2006 May 2.

PubMed ID

16632356 [ View in PubMed

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Abstract

A new class of tumor necrosis factor alpha (TNF-alpha) synthesis inhibitors based on an N-2,4-pyrimidine-N-phenyl-N'-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar activity against lipopolysaccharide stimulated TNF-alpha production. X-ray co-crystallization studies with mutated p38alpha showed that these trisubstituted ureas interact with the ATP-binding pocket in a pseudo-bicyclic conformation brought about by the presence of an intramolecular hydrogen bonding interaction.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
3-(2-CHLOROPHENYL)-1-(2-{[(1S)-2-HYDROXY-1,2-DIMETHYLPROPYL]AMINO}PYRIMIDIN-4-YL)-1-(4-METHOXYPHENYL)UREA	Mitogen-activated protein kinase 14	IC 50 (nM)	92	N/A	N/A	Details