Pharmacophore<br />
There are three functional groups that are the most important parts for the bioactivity of ARBs, see figure 1 for details.<br />
The first one is the imidazole ring that binds to amino acids in helix 7 (Asn). The second group is the biphenyl-methyl group that binds to amino acids in both helices 6 and 7 (Phe, Phe, Trp and His). The third one is the tetrazole group that interacts with amino acids in helices 4 and 5 (Arg and Lys). <br />
The tetrazole group has been successfully replaced by a carboxylic acid group as is the case with telmisartan. 
Structure-activity relationship (SAR)<br />
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, COH or NHSOCF 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. <br />
In valsartan, the imidazole ring of losartan has been replaced with an acylated amino acid.<br />
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. <br />
The structure of eprosartan is the one that differs most from the other ARBs, the usual biphenyl-methyl group has been replaced by a carboxy benzyl group that mimics more closely the phenolic moiety of Tyr group of Ang II. This change results in a stronger binding to the receptor but the biochemical and physiological effects are not significantly improved. <br />
Telmisartan has a carboxylic acid at the 2-position of the biphenyl-methyl group and is more potent than the tetrazole analogue. <br />
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.<br />
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.<br />
These results show that a medium-sized hydroxy alkyl group, such as CHMeOH and CMeOH, is favorable for the substituent of the 4-position on the imidazole ring. Furthermore, the ionizable group is favorable for the binding affinity.
Candesartan and olmesartan have the highest affinity for the AT receptors, followed by irbesartan and eprosartan. Valsartan, telmisartan and EXP 3174 have similar affinities that are about ten-fold less than that of candesartan. Losartan has the least affinity. ARBs' affinity for the AT receptor is generally much lower (or around 10,000 times less) than for the AT subtype. Therefore, they allow unhindered stimulation of the AT receptor.