Nonpeptidic angiotensin II AT1 receptor antagonists derived from 6-substituted aminocarbonyl and acylamino benzimidazoles

• Both 6-substituted aminocarbonyl and acylamino benzimidazole derivatives were designed and synthesized.
• Most compounds exhibited nanomolar AT1 receptor binding affinity and high AT1 receptor selectivity over AT2 receptor.
• Compounds 6f and 11g are orally active AT1 receptor antagonists.

Both 6-substituted aminocarbonyl and acylamino benzimidazole derivatives were designed and synthesized as nonpeptidic angiotensin II AT1 receptor antagonists. Compounds 6f, 6g, 11e, 11f, 11g, and 12 showed nanomolar AT1 receptor binding affinity and high AT1 receptor selectivity over AT2 receptor in a preliminary pharmacological evaluation. Among them, the two most active compounds 6f (AT1 IC50 = 3 nM, AT2 IC50 > 10,000 nM, PA2 = 8.51) and 11g (AT1 IC50 = 0.1 nM, AT2 IC50 = 149 nM, PA2 = 8.43) exhibited good antagonistic activity in isolated rabbit aortic strip functional assay. In addition, they were orally active AT1 receptor antagonists in spontaneous hypertensive rats.

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