Translations:Discovery and development of angiotensin receptor blockers/37/en

Structure-activity relationship (SAR)
Most of the ARBs have the same pharmacophore so the difference in their biochemical and physiological effects is mostly due to different substituents. Activity of a drug is dependent of its affinity for the substrate site and the length of time it binds to the site. Lipophilic substituents like the linear alkyl group at the 2-position on the imidazole ring together with the biphenyl-methyl group, associate with hydrophobic pockets of the receptor. An acidic group like tetrazole, CO₂H or NHSO₂CF₃ at the 1-position of the biphenyl-methyl group will bind to a basic position in the receptor and are required for potent antagonistic activity.
In valsartan, the imidazole ring of losartan has been replaced with an acylated amino acid.
Several substituents have been tried at the 4- and 5- positions on the imidazole ring. The chloro and hydroxymethyl groups connected to these positions in losartan are probably not of much importance in receptor binding since the other ARBs do not possess these functional groups and have comparable or better binding affinities than losartan. Irbesartan has a carbonyl group at the 5-position, functioning as a hydrogen bond acceptor in place of the hydroxymethyl group of losartan, resulting in a longer binding to the receptor.
The structure of eprosartan is the one that differs most from the other ARBs, the usual biphenyl-methyl group has been replaced by a carboxy benzyl group that mimics more closely the phenolic moiety of Tyr⁴ group of Ang II. This change results in a stronger binding to the receptor but the biochemical and physiological effects are not significantly improved.
Telmisartan has a carboxylic acid at the 2-position of the biphenyl-methyl group and is more potent than the tetrazole analogue.
It has been reported that imidazoles that have hydroxymethyl and carboxy groups at the 4- and 5 position, possessed potent antagonistic activity, caused by the hydrogen bonding and hydrophilicity of the hydroxymethyl group.
It has also been reported that an hydroxy group in the 4-position on the imidazole ring, plays an important role in the binding affinity and compensates for the disadvantage of lipophilicity of the bulky alkyl group.
These results show that a medium-sized hydroxy alkyl group, such as CHMeOH and CMe₂OH, is favorable for the substituent of the 4-position on the imidazole ring. Furthermore, the ionizable group is favorable for the binding affinity.