title: Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones.
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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285-0001.
authors.forename: D K
authors.initials: DK
authors.lastname: Herron
authors.forename: T
authors.initials: T
authors.lastname: Goodson
authors.forename: N G
authors.initials: NG
authors.lastname: Bollinger
authors.forename: D
authors.initials: D
authors.lastname: Swanson-Bean
authors.forename: I G
authors.initials: IG
authors.lastname: Wright
authors.forename: G S
authors.initials: GS
authors.lastname: Staten
authors.forename: A R
authors.initials: AR
authors.lastname: Thompson
authors.forename: L L
authors.initials: LL
authors.lastname: Froelich
authors.forename: W T
authors.initials: WT
authors.lastname: Jackson
mesh_terms: D000098:Acetophenones / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D009504:Neutrophils / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018102:Receptors, Leukotriene B4; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000098:Acetophenones; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; D007975:Leukotriene B4; C063823:LY 255283