LEUKOTRIENE B-4 (LTB(4)) RECEPTOR ANTAGONISTS - A SERIES OF (HYDROXYPHENYL) PYRAZOLES

A series of (hydroxyphenyl)pyrazoles was designed by molecular modelin g comparison with the LTB(4) structure and prepared for evaluation as LTB(4) receptor antagonists, culminating in etrazol-5-yl)heptyl]oxy]-2 -(1H-pyrazol-3-yl)phenyl (2). Using an assay for inhibition of specifi c [H-3]LTB(4) binding to human PMN, it was found that the pyrazole rin g could be methylated at N(1) with little loss of activity while methy lation at N(2) reduced activity significantly. The structure-activity relationship of the terminal acid group was investigated. Good activit y was found with o- and m-phenylalkanoic acids, chromane carboxylic ac id, and tetrazole groups. The best in vitro activity was realized with the pyrazole nitrogen unsubstituted and with a six-carbon chain linki ng 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 furth er preclinical evaluation.