Pharmacological Potential of p38 MAPK Inhibitors

GlaxoSmithKline, UP1340, 1250 South Collegeville Rd., P.O. Box 5089, Collegeville,

PA 19426-0989, USA

[email protected]

1 Introduction 66

2 Discovery of p38 Inhibitors 68

3 Regulation of Cytokine Expression 71

4 Data with p38 Inhibitors 73

4.1 Rheumatoid Arthritis 73

4.1.1 In Vitro Data Supporting a Role for p38a MAPK in RA 74

4.1.2 In Vivo Data Supporting a Role for p38 MAPK in RA 75

4.2 Pulmonary Disease 76

4.2.1 In Vitro Data Supporting p38 MAPK Activation in Pulmonary Disease. ... 76

4.2.2 In Vivo Data Supporting p38 MAPK Activation in Pulmonary Disease 76

4.3 Neurodegeneration 77

4.3.1 In Vitro Data Supporting a Role for p38 MAPK in Neurodegeneration . ... 77

4.3.2 In Vivo Data Supporting p38 MAPK Activation in Neurodegeneration 78

4.4 Other Indications 78

5 Conclusion 78

References 79

Abstract A key component of the intracellular signaling pathways involved in cellular response to environmental stress and inflammatory cytokines is the p38 family of mitogen-activated protein kinases (MAPKs). Of the four isoforms of the p38 family of MAPKs identified thus far, p38a is the most characterized enzyme. Since the discovery of p38a MAPK as a target of a series of compounds that inhibited the production of inflammatory cytokines, an intense effort has been applied to further identify, develop, and refine highly potent and selective inhibitors of this enzyme. In addition, availability of p38a MAPK inhibitors has allowed the investigators to dissect this signaling pathway and to examine its role in various pathologies. A large body of biochemical as well as genetic evidence indicates a critical role of p38a MAPK in both the production of inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF) and subsequent signaling initiated in response to these cytokines. This suggests that inhibition of p38a MAPK pathway will have utility in pathological settings where tissue inflammation and pro-inflammatory cy-tokines have been implicated. Indeed, several p38a MAPK inhibitors have been shown to be efficacious in preclinical animal models of a variety of diseases, including rheumatoid arthritis, pulmonary diseases, neuronal protection, and cancer. In the past few years, several groups have advanced inhibitors into early clinical studies for rheumatoid arthritis, but none thus far has reached the critical phase III efficacy stage. In this chapter, we re view the p38 MAPK pathway and pharmacological potential of p38a MAPK inhibitors in various pathologies with particular emphasis on inflammatory diseases.

Keywords p38 MAPK • Inhibitors • Inflammation • Interleukin 1 • Tumor necrosis factor • Cytokines • Rheumatoid arthritis • Respiratory • Neuronal

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