Structure-activity relationship study of some triazolinone based compounds with antagonistic balanced activity on angiotensin II receptor subtypes AT1 and AT2. A three-dimensional quantitative structure-activity relationship investigation.

Angiotensin II (AII) receptor antagonists have attracted much attention as anti-hypertensive agents in recent times following the discovery of side effects associated with angiotensin converting enzyme (ACE) inhibitors. Various lead structures of the compounds of this category are reported in the literature. Studying the structure-activity relationships (SAR) for such compounds has been a fascination for scientists and efforts have been made to identify the essential physico-chemical requirements for the angiotensin type 1 (AT1) receptor selective, angiotensin type 2 (AT2) receptor selective and some AT,/ AT2 balanced antagonistic activity compounds. With an aim to identify the structural requirements for balanced activity and differentiate between the features individually responsible for AT1 and AT2 antagonistic activities, a quantitative SAR (QSAR) analysis was carried out on a series of triazolinone based balanced AII receptor antagonists. The statistically significant equations with r > 0.88, chance < 0.01, q2 > 0.60 and F values at least three times greater than those reported were obtained for both AT1 and AT2 receptor subtypes antagonistic activities. A comparative study of the parameters responsible for AT1 and AT2 receptor antagonistic activities is carried out in order to identify the features that can be modulated to obtain balanced compounds. It has been observed that the most reliable equations obtained in the study show the contribution of hydrophobic parameters: logarithm of partition coefficient (logP), thermodynamic parameters: bend energy (Eb), and electronic parameters: electronic energy (Eelec) parameters towards AT1 anatgonistic activity, and thermodynamic parameters: total energy (E), steric parameters: principal moment of inertia along the Y-axis (PMIY) and electronic parameters: electronic energy (Eelec) parameters towards AT2 antagonistic activity. The parameter Eelec is common but its effect towards the two activities is opposite, negative for AT1 and positive for AT2.