Angiotensin II receptor antagonists

Abstract

The development of novel non-peptide compounds with high affinity for-angiotensin II (Ang II) receptors has greatly facilitated the subclassification of Ang II receptors into AT1- and AT2-receptor subtypes. Whereas PD 123177 (1-(4-amino-3-methylphenyl)methyl-5-diphenyl-acetyl-4,5,6,7-tetrahydro- 1H-imidazol [4,5-c]pyridine-6-carboxylic acid) is the prototypical antagonist for AT2-receptors, DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl) methyl) imidazole, losartan) is the prototypical antagonist for AT1-receptors. So far, non-selective non-peptide Ang II receptor antagonists have not been identified although AT1/AT2 selectivity ratios of 17 and 37 have already been reported for BIBS 39 (4'-[(2-n-butyl-6- cyclohexylaminocarbonylamino-benzimidazole-1-yl)-methyl] biphenyl-2-carboxylic acid) and BIBS 222 (2-n-butyl-1-[4-(6-carboxy-2, 5-dichlorobenzoylamino)-benzyl]-6-N-(methylaminocarbonyl)- n-pentylaminobenzimidazole). Functional studies with AT1-antagonists indicate that Ang II antagonism at the receptor level can be rather complex. Experimental data suggests that not only are receptor binding kinetics involved, but also that additional binding sites, and possibly even AT1 subtypes, are involved. The antihypertensive activity of the AT1-antagonist DuP 753 is demonstrated in a high renin (2K 1C) and a low renin (TGRmREN2) hypertensive rat model. The kidney especially is very sensitive to Ang II and this organ seems to be a target for Ang II receptor antagonists. This can be demonstrated with experiments on the isolated rat kidney.