Successful Structure-Based Design of Recent p38 MAP Kinase Inhibitors

Solveigh   C.   Karcher; Stefan   A.   Laufer

Abstract

Inflammation is a complex immune response to cellular and tissue damage caused by physical, chemical, immunological, or microbial stimuli [1]. Prior to the successful launch of the anti-cytokine biologics [2-4], therapeutic approaches for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease were associated with severe side effects. Although biological agents have revolutionized the treatment of inflammatory disorders, the high costs and inconvenient dosing regimens would greatly benefit from novel safe and effective orally active inhibitors of tumor necrosis factor (TNF) α and interleukin (IL) 1β. The clinical benefit of anticytokine therapy [5] and the central role of the p38 mitogen-activated protein (MAP) kinase in up-regulation of proinflammatory cytokines such as IL-1β and TNF-α [6] suggest that p38 MAP kinase is a promising target for antiinflammatory therapy [7-14]. Since 1993 an immense number of inhibitors of p38 MAP kinase have been characterized. To date, aside from the well known pyridinylimidazoles, multiple novel scaffolds have been identified, but only a small number have advanced into clinical phase II studies [15], probably due to high toxicity and poor selectivity [16]. To gain safe drug profiles, high potency, marginal CYP450 (cytochrome P450) interaction and toxicity, as well as high levels of selectivity would be desirable. This review will summarize current knowledge on p38 MAP kinase inhibitors and will critically discuss proceedings and strategies toward achieving selectivity and potency.

Keywords: p38 MAP kinase, p38 inhibitors, selectivity, potency, binding modes, DFG-in, DFG-out

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