Abstract
Arachidonic acid (ARA) undergoes enzyme-mediated oxidative metabolism, resulting in the formation of a number of biologically active metabolites. For over a century, these biochemical transformations have been the target of numerous pharmacological drugs for inflammation and pain. In particular, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors (coxibs) are widely used in the treatment of inflammation and pain. However, gastrointestinal (GI) and cardiovascular adverse effects of NSAIDs and coxibs, and recent findings demonstrating that there are significant risks from the disruption of oxylipin levels when pharmacologically inhibiting a single ARA cascade metabolic pathway, have led to studies involving the simultaneous inhibition of multiple pathways in ARA cascade. These studies suggest that multitarget inhibition represents a new and valuable option to enhance efficacy or reduce side-effects in the treatment of inflammation and pain. This review focuses on the crosstalk within the three pathways of the ARA cascade (cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450)), and summarizes the current and future approaches of multitarget inhibitors for the treatment of eicosanoid driven inflammation and pain.
Keywords: Cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 (CYP), soluble epoxide hydrolase (sEH), multitarget inhibitors, dual inhibitors
Current Medicinal Chemistry
Title:Rationally Designed Multitarget Agents Against Inflammation and Pain
Volume: 20 Issue: 13
Author(s): S. H. Hwang, A. T. Wecksler, K. Wagner and B. D. Hammock
Affiliation:
Keywords: Cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 (CYP), soluble epoxide hydrolase (sEH), multitarget inhibitors, dual inhibitors
Abstract: Arachidonic acid (ARA) undergoes enzyme-mediated oxidative metabolism, resulting in the formation of a number of biologically active metabolites. For over a century, these biochemical transformations have been the target of numerous pharmacological drugs for inflammation and pain. In particular, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) selective inhibitors (coxibs) are widely used in the treatment of inflammation and pain. However, gastrointestinal (GI) and cardiovascular adverse effects of NSAIDs and coxibs, and recent findings demonstrating that there are significant risks from the disruption of oxylipin levels when pharmacologically inhibiting a single ARA cascade metabolic pathway, have led to studies involving the simultaneous inhibition of multiple pathways in ARA cascade. These studies suggest that multitarget inhibition represents a new and valuable option to enhance efficacy or reduce side-effects in the treatment of inflammation and pain. This review focuses on the crosstalk within the three pathways of the ARA cascade (cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450)), and summarizes the current and future approaches of multitarget inhibitors for the treatment of eicosanoid driven inflammation and pain.
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Cite this article as:
Hwang S. H., Wecksler A. T., Wagner K. and Hammock B. D., Rationally Designed Multitarget Agents Against Inflammation and Pain, Current Medicinal Chemistry 2013; 20 (13) . https://dx.doi.org/10.2174/0929867311320130013
DOI https://dx.doi.org/10.2174/0929867311320130013 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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