Indole-based heterocyclic inhibitors of p38α MAP kinase: designing a conformationally restricted analogue

p38α Mitogen Activated Protein Kinase (MAP kinase) is an intracellular soluble serine threonine kinase. p38α kinase is activated in response to cellular stresses, growth factors and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α). The central role of p38α activation in settings of both chronic and acute inflammation has led efforts to find inhibitors of this enzyme as possible therapies for diseases such as rheumatoid arthritis, where p38α activation is thought to play a causal role. Herein, we report structure–activity relationship studies on a series of indole-based heterocyclic inhibitors that led to the design and identification of a new class of p38α inhibitors.