CONFORMATIONALLY RESTRICTED POLYSUBSTITUTED BIPHENYL DERIVATIVES WITH ANGIOTENSIN-II RECEPTORS ANTAGONIST PROPERTIES

被引:32
作者
BOVY, PR [1 ]
COLLINS, JT [1 ]
OLINS, GM [1 ]
MCMAHON, EG [1 ]
HUTTON, WC [1 ]
机构
[1] SEARLE,RES & DEV,ST LOUIS,MO 63198
关键词
D O I
10.1021/jm00112a015
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The synthesis and in vitro activity of new nonpeptide angiotensin II antagonists is presented. Compared to previously reported biphenyl compounds, the new analogues 8 and 9 have reduced conformational freedom derived from steric hindrance. Methyl 4'-methy-2',6'-dimethoxy[1,1'-biphenyl]-2-carboxylate 4 has been synthesized by a Von Pechmann condensation of orcinol with oxocyclohexane-2-carboxylate followed by dehydrogenation. This scheme provided the carbon skeleton of the biphenyl potentially substituted on the 2-, 2'-, 4'-, and 6'-positions. Elaboration of the subsituents led to a biphenyl derivative used to alkylate a 2-n-butyl-4-chloro-5-(hydroxymethyl)imidazole. After coupling with the imidazole two regioisomers were separated and identified by H-1 NMR. NOESY experiments were useful to establish regiochemistry of the final products that have angiotensin II blocking activity. Their affinity for angiotensin II receptors was established in a binding assay experiment and in an isolated organ test. The presence of 2',6'-dimethoxy substituent on the biphenyl moiety of the antagonist was found to significantly decrease affinity for the receptor.
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收藏
页码:2410 / 2414
页数:5
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