Leukotriene B4 (LTB4) receptor antagonists: a series of (hydroxyphenyl)pyrazoles.
J Med Chem
; 37(15): 2411-20, 1994 Jul 22.
Article
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| MEDLINE
| ID: mdl-8057289
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Receptores de Leucotrieno B4
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1994
Tipo del documento:
Article