Continued exploration of the triazolopyridine scaffold as a platform for p38 MAP kinase inhibition

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Abstract

The structure based drug design, synthesis and structure–activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.

Graphical abstract

The structure based drug design, synthesis and structure–activity relationship of a series of C6 sulfur linked triazolopyridine based p38 inhibitors are described. The metabolic deficiencies of this series were overcome through changes in the C6 linker from sulfur to methylene, which was predicted by molecular modeling to be bioisosteric. X-ray of the ethylene linked compound 61 confirmed the predicted binding orientation of the scaffold in the p38 enzyme.

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Present address: Genomics Institute of the Novartis Research Foundation (GNF), 10675 John Jay Hopkins Dr., San Diego, CA 92121, USA.

Present address: Johnson & Johnson PRD-La Jolla, 3210 Merryfield Row, San Diego, CA 9212, USA.

§

Present address: Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA.

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