AT1 Receptor Ligands: Virtual-Screening-Based Design with TOPP Descriptors, Synthesis, and Biological Evaluation of Pyrrolidine Derivatives

As a continuing effort to establish the structure–activity relationships (SARs) within the series of the angiotensin II antagonists (sartans), a pharmacophoric model was built by using novel TOPP 3D descriptors. Statistical values were satisfactory (PC4: r2=0.96, q2(5 random groups)=0.84; SDEP=0.26) and encouraged the synthesis and consequent biological evaluation of a series of new pyrrolidine derivatives. SAR together with a combined 3D quantitative SAR and high‐throughput virtual screening showed that the newly synthesized 1‐acyl‐N‐(biphenyl‐4‐ylmethyl)pyrrolidine‐2‐carboxamides may represent an interesting starting point for the design of new antihypertensive agents. In particular, biological tests performed on CHO‐hAT1 cells stably expressing the human AT1 receptor showed that the length of the acyl chain is crucial for the receptor interaction and that the valeric chain is the optimal one. A virtual approach that uses TOPP 3D descriptors to explore the AT1 receptor is presented. It features a new series of sartan analogues (shown), which were synthesized and biologically evaluated on CHO‐hAT1 cells stably expressing the human AT1 receptor.