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The inhibition of LTB(4) binding to and activation of G-protein-coupled receptors BLT1 and BLT2 is the premise of a treatment for several inflammatory diseases. In a lead optimization effort starting with the leukotriene B(4) (LTB(4)) receptor antagonist (2), members of a series of 3,5-diarylphenyl ethers were found to be highly potent inhibitors of LTB(4) binding to BLT1 and BLT2 receptors, with varying levels of selectivity depending on the substitution. In addition, compounds 33 and 38 from this series have good in vitro ADME properties, good oral bioavailability, and efficacy after oral delivery in guinea pig LTB(4) and nonhuman primate allergen challenge models. Further profiling in a rat non-GLP toxicity experiment provided the rationale for differentiation and selection of one compound (33) for clinical development.

The role of oxygen free radicals in the development of tissue injury and necrosis, including myocardial ischemic damage, is well documented. In this investigation, application of a free radical generator system (FRG) to rat myocardium resulted in ECG alterations typical of myocardial infarction; 24 hours after treatment, plasma lactate dehydrogenase (LDH) levels were elevated and 20% of the left ventricle was infarcted. In order to characterize the type of cellular damage and the ultrastructural changes in the affected cells, myocardial infarcts and myocardium from control rats were examined in the electron microscope.Six spontaneously hypertensive rats were lightly anesthetized with sodium pentobarbital and infused for 10 minutes through a carotid cannula near the ostium of the coronary artery. Three rats were infused with a FRG consisting of purine (2.3 mM), xanthine oxidase (0.02 μ/ml), and Fe -loaded transferrin (0.06 μM), and 3 sham-operated rats served as controls.