Potent triazolinone-based angiotensin II receptor antagonists with equivalent affinity for both the AT1 and AT2 subtypes

Structure-Activity Relationship Study of Some Triazolinone Based Compounds with Antagonistic Balanced Activity on Angio-tensin II Receptor Subtypes AT1 and AT2

“…1, 2 and 3, respectively [9]. A series of N 2 aryl triazolinone biphenyl sulfonamides with balanced antagonistic activity [8,10] have been reported in the literature which comply with the structure shown in Fig. 3.…”

“…Antagonism of the AT 1 receptor has been found to significantly increase the circulating levels of AII [8] through blockade of the negative feedback inhibition of renin release. These elevated levels of AII could have the potential to stimulate AT 2 receptors and then could lead to unidentified in vivo responses with possible deleterious effects.…”

Development of CoMFA models of affinity and selectivity to angiotensin II type-1 and type-2 receptors

“…Most of these regions are not seen in the model of AT 1 receptor affinity, which may indicate that the AT 2 receptor is more sensitive to steric bulk, at least for this data set. Many of the structural features that were found important for affinity and selectivity in the qualitative SAR [8,9] (some are shown in Fig. 7) are also seen in the contour plots.…”

“…1) and 62 quinazolinones (cf. 2) [18][19][20][21][22][23][24][25]. We reviewed the literature and selected only those publications where the binding affinity of these compounds was measured by a single protocol and were derived from the same laboratory.…”

“…It was speculated that these compounds would be useful as pharmacological tools and could prove valuable as therapeutic agents. Several series of compounds were synthesized by, for example, modifying the AT 1 selective antagonists to enhance the AT 2 affinity but no compounds with this profile have yet reached the market [8,9].…”