Leukotriene B4 Receptor Antagonists: The LY255283 Series of Hydroxyacetophenones

Article abstract of DOI:10.1021/jm00088a018

A series of hydroxyacetophenones was prepared for evaluation as leukotriene B₄ (LTB₄) receptor antagonists, culminating in 1-<5-ethyl-2-hydroxy-4-<<6-methyl-6-(1H-tetrazol-5-yl)heptyl>oxy>phenyl>ethanone (compound 35, LY255283).Using an assay for inhibition of specific <3H>LTB₄ binding to human PMN, we found that substitution of a nonpolar substituent in the 5-position was required for activity.Best activity was realized with hydrogen in the 3-position, hydroxyl in the 2-position, short chain alkyl ketone in the 1-position, and a six- or eight-carbon chain linking the oxygen in the 4-position with an unsaturated terminal function.Compound 35, having an IC50 of 87 nM in the binding assay, was chosen for further preclinical evaluation.