SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 1-ACYL-4-((2-METHYL-3-PYRIDYL)CYANOMETHYL)PIPERAZINES AS PAF ANTAGONISTS

被引:39
作者
CARCELLER, E
MERLOS, M
GIRAL, M
ALMANSA, C
BARTROLI, J
GARCIARAFANELL, J
FORN, J
机构
[1] J URIACH & CIA SA,RES CTR,CHEM & PHARMACOL LABS,DEGA BAHI 59-67,E-08026 BARCELONA,SPAIN
[2] J URIACH & CIA SA,RES CTR,DEPT CHEM,CHEM & PHARMACOL LABS,E-08026 BARCELONA,SPAIN
[3] J URIACH & CIA SA,RES CTR,DEPT PHARMACOL,CHEM & PHARMACOL LABS,E-08026 BARCELONA,SPAIN
关键词
D O I
10.1021/jm00072a019
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A second generation of (cyanomethyl)piperazines, 1-acyl-4-((2-methyl-3-pyridyl)cyanomethyl)-piperazines, with increased oral activity was prepared and evaluated in vitro in a PAF-induced platelet aggregation assay (PAG) and in vivo in a PAF-induced hypotension test in normotensive rats (HYP). Oral activity was ascertained through a PAF-induced mortality test in mice (MOR). Attachment of a methyl group at position 2 of our earlier pyridine derivatives resulted in an improvement of 1 order of magnitude or greater in the ID50 of the oral test. Three different types of acyl substituents of similar potency emerge from this work: N-(diphenylmethylamino)acetyl, 3-substituted 3-hydroxy-3-phenylpropionyl, and N-substituted 3-amino-3-phenylpropionyl groups. The most interesting compounds, 26 (UR-12460, PAG IC50 = 0.040 muM, HYP, ID50 = 0.021 mg/kg iv, MOR, ID50 = 0.30 mg/kg po) and 58 (UR- 12519, PAG IC50 = 0.041 muM, HYP, ID50 = 0.015 mg/kg iv, MOR, ID50 = 0.044 mg/kg po), compare favorably with WEB-2086. Compounds 26 and 58 were also tested in active anaphylactic shock (AAS) and endotoxin-induced mortality (EIM) tests. On the basis of these data, compounds 26 and 58 have been selected for further pharmacological development.
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页码:2984 / 2997
页数:14
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