Synthesis, crystal structure, and activity of pyrazole-based inhibitors of p38 kinase.

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Graneto MJ, Kurumbail RG, Vazquez ML, Shieh HS, Pawlitz JL, Williams JM, Stallings WC, Geng L, Naraian AS, Koszyk FJ, Stealey MA, Xu XD, Weier RM, Hanson GJ, Mourey RJ, Compton RP, Mnich SJ, Anderson GD, Monahan JB, Devraj R

Synthesis, crystal structure, and activity of pyrazole-based inhibitors of p38 kinase.

J Med Chem. 2007 Nov 15;50(23):5712-9. Epub 2007 Oct 19.

PubMed ID

17948975 [ View in PubMed

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Abstract

A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme. New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles. Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules. The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38 alpha. A compound identified from this series was efficacious in an animal model of rheumatic disease.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINE	Mitogen-activated protein kinase 14	IC 50 (nM)	600	7.5	30	Details