Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres.

doi:10.1021/JM960547H

Paper

Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres.

Published Dec 20, 1996 · Y. Kohara, K. Kubo, E. Imamiya

Journal of medicinal chemistry

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263

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1

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Abstract

The design, synthesis, and biological activity of benzimidazole-7-carboxylic acids bearing 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, 5-thioxo-1,2,4-oxadiazole, and 2-oxo-1,2,3,5-oxathiadiazole rings are described. These compounds were efficiently prepared from the key intermediates, the amidoximes 4. The synthesized compounds were evaluated for in vitro and in vivo angiotensin II (AII) receptor antagonistic activities. Most were found to have high affinity for the AT1 receptor (IC50 value, 10(-6)-10(-7)M) and to inhibit the AII-induced pressor response (more than 50% inhibition at 1 mg/kg po). The 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, and 5-thioxo-1,2,4-oxadiazole derivatives showed stronger inhibitory effects than the corresponding tetrazole derivatives, while their binding affinities were weaker. This might be ascribed to their improved bioavailability by increased lipophilicity. The 5-oxo-1,2,4-oxadiazole derivative 2 (TAK-536) and 5-oxo-1,2,4-thiadiazole derivative 8f showed efficient oral bioavailability without prodrug formation. This study showed that the 5-oxo-1,2,4-oxadiazole ring and its thio analog, the 5-oxo-1,2,4-thiadiazole ring, could be lipophilic bioisosteres for the tetrazole ring in nonpeptide AII receptor antagonists.

In Vitro Study

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Study Snapshot

The 5-oxo-1,2,4-oxadiazole and 5-thioxo-1,2,4-oxadiazole rings can serve as lipophilic bioisosteres for tetrazole rings in nonpeptide angiotensin II receptor antagonists.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres.

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References

Citations

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