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:epartment of Entomology and Comprehensive Cancer Center, University of California, Davis, One shields avenue, Davis, CA 95616-8584, USA.
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.
