Oral 5lipoxygenaseactivating protein inhibitors

An oral small molecule inhibitor of 5-lipoxygenase-activating protein (FLAP), DG-031, of unknown structure, is in clinical trials with CHD patients. FLAP inhibitors are anticipated to reduce proinflammatory leukotriene mediators such as the potent chemotactic agent, LTB4 (Figure 6). In a 4-week phase II trial in patients with a previous history of MI, DG-031 (250, 500, and 750 mg day" 1 p.o.) at the highest dose reduced serum LTB4 (26%) and MPO (12%) levels as well as soluble intercellular adhesion molecule. As discussed previously, MPO and LTB4 are inflammatory markers associated with a higher risk of CHD. Plasma CRP levels were also reduced at the highest dose, but the response did not reach statistical significance. Accompanying these changes, LDLc levels increased slightly, by 8% with the highest dose.92 These results represent the first demonstration that two key biomarkers of inflammation were reduced following oral dosing with an anti-inflammatory agent in a CHD patient population. It remains to be seen whether these biomarker results translate to a corresponding benefit in actual clinical events, especially given the absence of any profound changes in LDLc, in phase III trials.

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