Design, synthesis, and antihypertensive evaluation of 2 '-tetrazolyl and 2 '-carboxy-biphenylylmethyl-pyrrolidine scaffolds substituted at their N-1, C-3, and C-4 positions as potential angiotensin II AT(1) receptor antagonists

Abstract

A series of novel 2-tetrazolyl- and 2-carboxy-biphenylylmethyl-pyrrolidine derivatives (VIIIa-d, IX, X, XIa-d, XII, XIII, XIVa-d, XV,and XVI) were designed and evaluated as Ang II AT1 receptor antagonists. The compare/fit scores of these molecules were determined using an Ang II AT1 receptor antagonist hypothesis constructed from known antagonists using CATALYST/DS modules and demonstrated significantly high simulated fit values. These hit molecules were subsequently synthesized and their in vivo antihypotensive and antihypertensive activities evaluated in normotensive cats and rats, and hypertensive rats. Compounds XII, XIII, XV, and XVI showed lower or similar levels of activity to the reference compound losartan. In contrast, the activities of compounds X and IX were 1.5- and 2-fold higher than losartan. Furthermore, the LD50 value for IX was determined to be 117 μg/Kg, indicating its high safety margin.