Piperidine-based heterocyclic oxalyl amides as potent p38α MAP kinase inhibitors

The design and synthesis of a new class of p38α MAP kinase inhibitors based on 4-fluorobenzylpiperidine heterocyclic oxalyl amides are described. Many of these compounds showed low-nanomolar activities in p38α enzymatic and cell-based cytokine TNFα production inhibition assays. The optimal linkers between the piperidine and the oxalyl amide were found to be [6,5] fused ring heterocycles. Substituted indoles and azaindoles were favored structural motifs in the cellular assay.

Graphical abstractA new class of p38α MAP kinase inhibitors based on 4-fluorobenzylpiperidine substituted heterocycles is described. Optimal features include a piperidine and an oxalyl amide separated by a [6,5] fused ring heterocycle.Figure optionsDownload full-size imageDownload as PowerPoint slide