Clinically Studied Inhibitors 31 5LO and FLAP inhibitors

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Zileuton (1) is the only marketed 5-LO inhibitor and is approved for the treatment of asthma [44]. The treatment of mild asthmatics with zileuton (600 mg qid, 2 weeks) resulted in a 96% increase in plasma thromboxane B2 from baseline levels and a corresponding 62% increase in spontaneous platelet aggregation, suggesting a shunting of arachidonic acid metabolism to the cyclooxygenase pathway [45]. In a small clinical trial, zileuton provided a magnitude of prophylaxis in exercise-induced asthma (as measured by FEV1) equivalent in magnitude but considerably shorter in duration than salmeterol, montelukast and zafirlukast [46]. Zileuton inhibited bronchoalveolar lavage (BAL) fluid eosinophil counts by 68% upon antigen challenge in a sub-population of allergic asthmatics who exhibited a significant increase in BAL leukotrienes and inflammatory cytokines, but not in those patients where leukotriene levels were unchanged upon antigen challenge [47]. Zileuton provided minimal efficacy [48] or no effect [49] in aspirin-induced respiratory reactions. A pilot clinical study for the treatment of acne demonstrated that zileuton (600 mg qid, 3 months) afforded a 71% mean reduction in inflammatory lesions, a 65% reduction of sebum lipids and a 59% decrease in the acne severity index [50]. The synthesis of sebum lipids upon zileuton treatment can be normalized after 2 weeks with inhibition levels similar to isotretinoin treatment [51]. Zileuton also exhibited efficacy in a pilot study of atopic dermatitis [52]. The weak, reversible inhibition of CYP1A2 has been identified as the mechanism whereby zileuton elicits clinically relevant drug interactions resulting in the decreased clearance of CYP1A2 substrates such as (R)-warfarin and pro-pranolol [53].

A number of FLAP inhibitors have demonstrated clinical efficacy in the treatment of asthma [1]; however, no FLAP inhibitor has achieved regulatory approval for this or any other indication. A new activity has been described for the clinically tested FLAP inhibitor MK-886 (2). MK-886 is an inhibitor (IC50 = 3.2 mM) of inducible rat microsomal prostaglandin E synthase-1 (mPGES-1) and, consistent with this activity, inhibits PGE2 production in IL-1 b stimulated chondrocyte lysates from osteoarthritis patients [54-56]. This inhibitory potency is > 100-fold less than its FLAP binding affinity, suggesting that the inhibition of mPGES-1 is not involved in the observed clinical efficacy of MK-886.

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The FLAP inhibitor BAY X 1005 (3) was tested in a pilot clinical COPD study (500 mg bid, 14 days) and produced modest reductions in sputum levels of LTB4 (48%) and myeloperoxidase (34%) although no change in total chemotactic activity was observed [57].



In a phase Ila trial, DG 031 (BAY X 1005, 250 mg qd, bid or tid for 4 weeks), a FLAP inhibitor previously in the clinic for asthma and the first to be tested clinically for cardiovascular indications, suppressed the production of LTB4 and

reduced levels of biomarkers (MPO and sICAM-1) that may be linked to arterial inflammation and heart attack risk [58].

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