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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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
CARINI, DJ
DUNCIA, JV
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
DUNCIA, JV
JOHNSON, AL
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
JOHNSON, AL
CHIU, AT
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
CHIU, AT
PRICE, WA
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
PRICE, WA
WONG, PC
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
WONG, PC
TIMMERMANS, PBMW
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
CARINI, DJ
DUNCIA, JV
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
DUNCIA, JV
JOHNSON, AL
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
JOHNSON, AL
CHIU, AT
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
CHIU, AT
PRICE, WA
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
PRICE, WA
WONG, PC
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880
WONG, PC
TIMMERMANS, PBMW
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DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880DUPONT CO INC,DEPT MED PROD,CARDIOVASC PHARMACOL SECT,EXPTL STN,WILMINGTON,DE 19880