A Novel Series of Selective, Non-Peptide Inhibitors of Angiotensin II Binding to the AT2 Site

Article abstract of DOI:10.1021/jm00077a001

The availability of peptide and non-peptide Ang II receptor antagonists has permitted the study of Ang II receptor heterogeneity.It is now widely recognized that there are at least two distinct Ang II receptor subtypes.AT₁ receptors are selective in their recognition of agents such as losartan, DuP 532,L-158,809,SK<*>F108566, and similar non-peptides.To date, all of the well-known actions of Ang II in mammals are blocked by the AT₁ selective antagonists such as losartan and are thus designated as being mediated by the AT₁ receptor.Although there have been reports of functional activity mediated through AT₂ sites, the pharmacological role for the AT₂ receptor has not yet been elucidated.Herein, we report the chemistry and SAR on a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids which have selective affinity for AT₂ receptors.The most potent of which (19) has an IC50 of 30 nM for the AT₂ receptor in the rat adrenal radioligand binding assay.