Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones.
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.
Herron
D K
DK
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285-0001.
Goodson
T
T
Bollinger
N G
NG
Swanson-Bean
D
D
Wright
I G
IG
Staten
G S
GS
Thompson
A R
AR
Froelich
L L
LL
Jackson
W T
WT
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*
D000098:Acetophenones; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; D013777:Tetrazoles; D007975:Leukotriene B4; C063823:LY 255283