Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones.
J Med Chem, 1992/5/15;35(10):1818-28.
Herron DK[1], Goodson T, Bollinger NG, Swanson-Bean D, Wright IG, Staten GS, Thompson AR, Froelich LL, Jackson WT
Affiliations
PMID: 1316967
Impact factor: 8.039
Abstract
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.
MeSH terms
Acetophenones; Humans; Leukotriene B4; Magnetic Resonance Spectroscopy; Neutrophils; Receptors, Immunologic; Receptors, Leukotriene B4; Structure-Activity Relationship; Tetrazoles
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