TAK-715 (Takeda) was a p38 MAPK inhibitor that had been implicated in the pro-inflammatory cytokine signal pathway, the inhibitors of which are potentially useful for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Inhibition of p38 MAPK and LPS-stimulated release of TNF-α from human monocytic THP-1 cells by TAK-715 was demonstrated in vitro; its inhibition of LPS-induced TNF-α production was demonstrated in vivo in mice. TAK-715 had showed good bioavailability in mice and rats and efficacy in a rat adjuvant-induced arthritis model. It was advanced into clinical Phase II trials but was discontinued, as it did not satisfy criteria for further development.

PH-797804 is a diarylpyridinone inhibitor of p38alpha mitogen-activated protein. The drug was developed by Pfizer for the treatment of inflammatory diseases. PH-797804 is being tested in phase II of clinical trials in patients with COPD, osteoarthritis, rheumatoid arthritis and post-herpetic neuralgia.

VX-702 is a highly selective inhibitor of p38α MAPK kinase, developed by Vertex Pharmaceuticals Inc in collaboration with Kissei Pharmaceuticals Co. Ltd for potential treatment of inflammation, rheumatoid arthritis and cardiovascular diseases. VX-702 was evaluated in two phase II clinical trials against rheumatoid arthritis, but its development was discontinued by Vertex.

VX-745 (Neflamapimod) is a brain-penetrant highly selective, orally bioavailable drug that inhibits the intracellular enzyme p38 mitogen-activated protein kinase alpha (MAPKa). It is currently in phase 2 clinical studies in patients with early Alzheimer's disease. The targeting of p38 MAPK by VX-745 was associated with the suppression of the release of inflammatory mediators, including interleukin (IL)-1β and tumor necrosis factor (TNF)α, known to be implicated in exacerbating the pathophysiology of rheumatoid arthritis (RA). The drug was in phase II of the clinical trial for RA, but that studies were discontinued.

Doramapimod (BIRB-796) is a p38 MAPK inhibitor, relatively potent against alpha isoform. Oral doramapimod exerts anti-inflammatory potential in humans in vivo. Doramapimod has entered clinical trials for the treatment of autoimmune diseases.