5-lipoxygenase inhibitors for the treatment of COPD.

Abstract

The potential for leukotrienes as mediators to target in the development of novel therapies for diseases such as COPD is underscored by their inflammatory behavior and the capacity of leukotriene receptor antagonists and synthesis inhibitors to reduce inflammatory responses when administered in vivo. Airway neutrophilia in COPD patients is believed to be a contributing source of inflammation and is associated with airway remodeling. The presence of neutrophils is mediated in part by leukotriene B(4) (LTB(4)), and the capacity for LTB(4) alone to replicate many aspects of neutrophilic inflammation has provided the focus of drug development toward its specific antagonism. More recently, the potential involvement of the monocyte-macrophage lineage in the etiology of COPD has received growing attention as a target for leukotriene inhibition. The future avenues for exploration of leukotriene inhibition could have been expanded by the realization that 5-lipoxygenase activity is primarily located at the nuclear membrane and the existence of differing cell surface and nuclear receptors to LTB(4). The success of compounds under development in this and other anti-inflammatory classes, however, depends as much on the evolution of clinical studies designed to test the "proof of concept" in efficacy through the examination of surrogate markers or physiologic readouts of changes in lung function.