SYNTHESIS AND ANGIOTENSIN-II RECEPTOR ANTAGONISTIC ACTIVITIES OF BENZIMIDAZOLE DERIVATIVES BEARING ACIDIC HETEROCYCLES AS NOVEL TETRAZOLE BIOISOSTERES

The design, synthesis, and biological activity of benzimidazole-7-carb oxylic 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 inte rmediates, the amidoximes 4. The synthesized compounds were evaluated for in vitro and in vivo angiotensin II (AII) receptor antagonistic ac tivities. Most were found to have high affinity for the AT(1) receptor (IC50 value, 10(-6)-10(-7)M) and to inhibit the AII-induced presser r esponse (more than 50% inhibition at 1 mg/kg po). The 5-oxo-1,2,4-oxad iazole, 5-oxo-1,2,4-thiadiazole, and 5-thioxo-1,2,4-oxadiazole derivat ives showed stronger inhibitory effects than the corresponding tetrazo le derivatives, while their binding affinities were weaker. This might be ascribed to their improved bioavailability by increased lipophilic ity. The 5-oxo-1,2,4-oxadiazole derivative 2 (TAK-536) and 5-oxo-1,2,4 -thiadiazole derivative of showed efficient oral bioavailability witho ut prodrug formation. This study showed that the 5-oxo-1,2,4-oxadiazol e ring and its thio analog, the 5-oxo-1,2,4-thiadiazole ring, could be lipophilic bioisosteres for the tetrazole ring in nonpeptide AII rece ptor antagonists.