Section review pulmonary-allergy, dermatological, gastrointestinal and arthritis: Development of drugs that suppress macrophages: Beginning of a new era?
Drugs, currently in development and targeted toward macrophages, are principally aimed at the down-regulation of macrophage function to treat the wide variety of diseases caused by excessive activity of these cells. The principal current strategy for developing such drugs lies in wedding conventional pharmacologic approaches of compound development to screening these compounds against monocytes/macrophages In vitro for their ability to inhibit selected functions/release of mediators. A majority of efforts now underway address developing compounds to inhibit cytokine release, particularly TNFα or IL-1. Another major goal is to develop compounds that suppress arachidonic acid metabolism in macrophages, via the cyclooxygenase (CO) or 5-lipoxygenase (5-LO) pathways. These approaches collectively emphasise a significant problem: In a given disease, is it better to inhibit release of only one selected mediator from macrophages or, rather, release of several? A clear answer to this question is not now available but will likely emerge in the next few years as testing of compounds currently in development proceeds. The approach we have taken at Macronex is first to develop a profile of desired mediators/functions of macrophages to be inhibited for each disease and then to screen (in a comprehensive, proprietary assay system of utilising seventeen human monocyte functions in vitro) for compounds which inhibit several or all of these selected mediators/functions. Results of this assay system to date indicate that even compounds which are closely related structurally can have disparate effects on macrophages and selectively inhibit one or multiple mediators/functions. 1994 © Ashley Publications Ltd.
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