Successful Structure-Based Design of Recent p38 MAP Kinase Inhibitors

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) alpha and interleukin (IL) 1beta. The clinical benefit of anti-cytokine therapy [5] and the central role of the p38 mitogen-activated protein (MAP) kinase in up-regulation of pro-inflammatory cytokines such as IL-1beta and TNF-alpha [6] suggest that p38 MAP kinase is a promising target for anti-inflammatory 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.

Developing small molecules to inhibit kinases unkind to the heart: p38 MAPK as a case in point

“…The α and β isoforms share a gatekeeper Threonine residue at position 106 (Thr 106) in both human and murine isoforms 4. This gatekeeper guards a hydrophobic (back)pocket(I) probed by the classic pyridinylimidazole inhibitors discovered to have anti-inflammatory activity through inhibition of this pathway almost two decades ago 5. The terms in parenthesis apply to the nomenclature adopted to describe the 5 sub-regions of ATP-binding site used in the design of ATP-competitive inhibitors 5.…”

“…This gatekeeper guards a hydrophobic (back)pocket(I) probed by the classic pyridinylimidazole inhibitors discovered to have anti-inflammatory activity through inhibition of this pathway almost two decades ago 5. The terms in parenthesis apply to the nomenclature adopted to describe the 5 sub-regions of ATP-binding site used in the design of ATP-competitive inhibitors 5. A number of other scaffolds that also rely on this gatekeeper have also been developed (see5–8 for reviews).…”

The Discovery of Novel Experimental Therapies for Inflammatory Arthritis

“…These results suggested that MEK blockade could be useful for attenuating proinflammatory cytokine synthesis as well as for suppressing osteoclast-mediated bone erosions in inflammatory arthritis. However, the “cross-talk” that is known to occur between the JAK/STAT and MEK/ERK pathway [28, 76] likely also creates an added layer of complexity for regulating osteoclast function in inflammatory arthritis since the JAK/STAT pathway has also been considered as a suitable target pathway for the suppression of inflammatory disorders [26]. In that regard, Kwak et al [77] showed that AG-490, an inhibitor of Jak2/Jak3 activity, actually induced osteoclast survival by activating both the MEK/ERK and PI3K/PTEN/Akt cell survival pathway.…”

“…A previously published compilation of review articles highlighted the recent advances in the identification of novel targets and cellular processes in RA, which included non-IL-1, non-TNF- α and non-IL-6 proinflammatory cytokines, chemokines, adhesion molecules, vascular endothelial growth factor and insulin-like growth factor-1, matrix metalloproteinases (MMPs), complement and pro- and antiapoptosis molecules [25] as well as the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway whereby the Jak3 inhibitor, CP690550 is the first small molecule inhibitor (SMI) to reach phase III clinical trials status [26], Mitogen-Activated Protein Kinase (MAPK) pathway [27, 28], and the IL-6/IL-6 receptor/gp130 complex [29, 30], all of which are applicable to additional basic and clinical studies wherein their future use in the medical intervention of adult and childhood RA and other inflammatory arthopathies may be further assessed. …”

Synthesis and Biological Testing of N‐Aminoimidazole‐Based p38α MAP Kinase Inhibitors

“…[8] Various well-known ATP-competitive MAPK inhibitors have since been developed which are derived from the prototype inhibitors SK&F 86002 and SB 203580 (Figure 1). [10][11][12] Various potent and selective p38a inhibitors are currently in phase II clinical studies for rheumatoid arthritis, psoriasis, inflammatory bowel diseases, neuropathic pain, cancer, depression, and cardiovascular diseases. [13] With respect to the pyridinylimidazoles, it was revealed that 2-sulfanylimidazoles offer advantages over SB 203580, such as fewer cytochrome P450 (CYP450) interactions and improved kinetic properties.…”