Imidazole-Based AT1 Receptor Ligands: Design, Synthesis and Pharmacological Evaluation.

The angiotensin II type 1 (AT1) receptor is a key component of the renin-angiotensin system (RAS) and a validated target for cardiovascular and renal disorders. Developing small molecules with defined AT1 versus AT2 binding profiles remains important for both therapeutic and mechanistic studies. Here, a series of novel imidazole-based compounds was synthesized and evaluated for their binding affinities toward angiotensin II type 1 (AT1) and type 2 (AT2) receptors. Binding studies were conducted by measuring the displacement of radiolabeled [3H]-angiotensin II ([3H]-AII) in PLC-PRF-5 human hepatoma cells for AT1 receptors and calf cerebellum membranes for AT2 receptors. Structure-activity relationship (SAR) analysis revealed that sulfonamide substitution significantly enhanced AT1 receptor affinity, whereas sterically hindered derivatives and ester-containing compounds were less active. Molecular docking studies using the AT1 receptor crystal structure (PDB: 8TH4) rationalized the observed activity trends. The most active compound showed high AT1 affinity (Ki = 5 nM), comparable to losartan, and all compounds displayed preferential binding for AT1 over AT2 receptors.