title: Leukotriene B4 (LTB4) receptor antagonists: a series of (hydroxyphenyl)pyrazoles.
abstract: A series of (hydroxyphenyl)pyrazoles was designed by molecular modeling comparison with the LTB4 structure and prepared for evaluation as LTB4 receptor antagonists, culminating in 4-ethyl-5-[[6-methyl-6-(1H-tetrazol-5-yl)heptyl]oxy]-2-(1H-pyrazol -3- yl)phenol (2). Using an assay for inhibition of specific [3H]LTB4 binding to human PMN, it was found that the pyrazole ring could be methylated at N(1) with little loss of activity while methylation at N(2) reduced activity significantly. The structure-activity relationship of the terminal acid group was investigated. Good activity was found with o- and m-phenylalkanoic acids, chromane carboxylic acid, and tetrazole groups. The best in vitro activity was realized with the pyrazole nitrogen unsubstituted and with a six-carbon chain linking the phenyl ether oxygen to the tetrazole group. Compound 2, having an IC50 of 6.4 +/- 0.8 nM in the binding assay, was selected for further preclinical evaluation.
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285.
authors.forename: R W
authors.initials: RW
authors.lastname: Harper
authors.forename: W T
authors.initials: WT
authors.lastname: Jackson
authors.forename: L L
authors.initials: LL
authors.lastname: Froelich
authors.forename: R J
authors.initials: RJ
authors.lastname: Boyd
authors.forename: T E
authors.initials: TE
authors.lastname: Aldridge
authors.forename: D K
authors.initials: DK
authors.lastname: Herron
mesh_terms: D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced / Q000188:drug therapy; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D011720:Pyrazoles; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine