title: Rationally designed multitarget agents against inflammation and pain.
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.
authors: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, One Shields Avenue, Davis, CA 95616-8584, USA.
authors: S H
authors: SH
authors: Hwang
authors: A T
authors: AT
authors: Wecksler
authors: K
authors: K
authors: Wagner
authors: B D
authors: BD
authors: Hammock
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D058990:Molecular Targeted Therapy / Q000379:methods; D010146:Pain / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases