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Therapeutic Potential of p38 MAP Kinase Inhibition in the Management of Cardiovascular Disease

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Abstract

p38 mitogen-activated protein kinases (p38 MAPKs) are key signalling molecules that regulate cellular behavior in response to environmental stresses. They regulate pro-inflammatory cytokines and therefore p38 MAPKs are implicated in the pathogenesis of many inflammatory-driven conditions, including atherosclerosis. Therapeutic inhibition of p38 MAPKs to attenuate inflammation has been the focus of comprehensive research in the last 2 decades, following the discovery of p38α as the molecular target of pyrindinyl imidazole compounds, which suppress the cytokines tumor necrosis factor-α and interleukin-1. The potential of p38 MAPK inhibitors was initially explored within archetypal inflammatory conditions such as rheumatoid arthritis and Crohn’s disease, but early studies demonstrated poor clinical efficacy and unacceptable side effects. Subsequent clinical trials evaluating different p38 MAPK inhibitor compounds in disease models such as chronic obstructive pulmonary disease (COPD) and atherosclerosis have shown potential clinical efficacy. This review aims to provide succinct background information regarding the p38 MAPK signaling pathway, a focus of p38 MAPKs in disease, and a brief summary of relevant pre-clinical studies. An update of human clinical trial experience encompassing a clinically orientated approach, dedicated to cardiovascular disease follows. It provides a current perspective of the therapeutic potential of p38 MAPK inhibitors in the cardiovascular domain, including safety, tolerability, and pharmacokinetics.

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Acknowledgments

JC is employed by Cambridge University Hospitals NHS Trust but is seconded to GSK for 50% of the time to conduct clinical trials (including those reviewed in this review). However, JC does not have any shares in GSK and does not receive any dividends, bonuses or personal grants from GSK. PRG owns stocks in AZ and GSK as part of a portfolio account that is managed by a third party. IBW has received grant support from GSK and the technology strategy board to work on p38 MAP kinase inhibitors. MF is in receipt of a GSK imaging fellowship. KMMP has no potential conflicts of interest that might be relevant to the content of this review. All the authors acknowledge the support received by the NIHR Biomedical Research Centre at Cambridge University Hospitals NHS Foundation Trust and the Cambridge Clinical Trials Unit. IBW and KMMP also acknowledge support from the British Heart Foundation.

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  1. Cambridge University Hospitals NHS Foundation Trust and Clinical Pharmacology Unit, University of Cambridge, Cambridge, UK

    Marie Fisk, Parag R. Gajendragadkar, Kaisa M. Mäki-Petäjä, Ian B. Wilkinson & Joseph Cheriyan

  2. Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    Ian B. Wilkinson & Joseph Cheriyan

  3. Addenbrooke’s Hospital, Box 110, Level 3, ACCI Building, Hills Road, Cambridge, CB2 0QQ, UK

    Joseph Cheriyan

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  1. Marie Fisk
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Correspondence to Joseph Cheriyan.

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Fisk, M., Gajendragadkar, P.R., Mäki-Petäjä, K.M. et al. Therapeutic Potential of p38 MAP Kinase Inhibition in the Management of Cardiovascular Disease. Am J Cardiovasc Drugs 14, 155–165 (2014). https://doi.org/10.1007/s40256-014-0063-6

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