text: For a simple overview of the development of ARBs, see figure 3.
  Because of saralasin, the first Ang II antagonist, and the development of the first ACE inhibitor captopril, it was generally acknowledged that Ang II receptor antagonists might be promising as effective antihypertensive agents.
  Saralasin was developed in the early 1970s and is an octapeptide analogue of Ang II, where the amino acids Asp, Ile and Phe have been replaced with Ser, Val and Ala, respectively. Saralasin was not orally bioavailable, had short duration of action and showed partial agonist activity and therefore it was not suitable as a drug.
  Thus the goal was to develop a smaller nonpeptide substance with similar inhibition and binding features. At this time, a group at DuPont had already started the screening of nonpeptide mimics of Ang II using existing substances from chemical libraries.
  Research investigators at Takeda discovered in 1982 the weak nonpeptide Ang II antagonists S-8307 and S-8308 from a group of 1-benzylimidazole-5-acetic acid derivatives. S-8307 and S-8308 have moderate potency, short duration of action and limited oral bioavailability, however they are selective and competitive AT receptor antagonists without partial agonist activity. A group at DuPont postulated that both Ang II and the Takeda leads were bound at the same receptor site. These two substances served as lead compounds for further optimization of AT receptor blockers.
  Using nuclear magnetic resonance studies on the spatial structure of Ang II, scientists at DuPont discovered that the Takeda structures had to be enlarged at a particular position to resemble more closely the much larger peptide Ang II. 
  Computer modeling was used to compare S-8308 and S-8307 with Ang II and it was seen that Ang II contains two acidic residues near the NH terminus. These groups were not mimicked by the Takeda leads and therefore it was hypothesized that acidic functional groups would have to be added to the compounds.<br />
  The 4-carboxy-derivative EXP-6155 had a binding activity which was ten-fold greater than that of S-8308 which further strengthened this hypothesis.
  By replacing the 4-carboxy-group with a 2-carboxy-benzamido-moiety the compound EXP-6803 was synthesized. It had highly increased binding affinity but was only active when administered intravenously.
  Replacing the 2-carboxy-benzamido-group with a 2-carboxy-phenyl-group created the lipophilic biphenyl-containing EXP-7711, which exhibited good oral activity but slightly less affinity for the AT receptor. <br />
  Then the polar carboxyl group was replaced with a more lipophilic tetrazole group in order to increase oral bioavailability and duration of action further and the compound thus formed was named losartan. This development took place in 1986 and losartan became the first successful Ang II antagonist drug, approved as such in the United States in 1995 and was marketed by Merck.
  This development was an extensive program and it is estimated that the process from the Takeda structures to the final substance, losartan, took more than fifty person-years of work in biological testing and chemical modifications. This represents an excellent investment given that a recent study estimated that losartan administration in the European union may reduce health care provision costs by 2.5 billion euro over 3.5 years.
  Using a different lead, optimization from S-8308, eprosartan was developed by SmithKline Beecham in 1992. Eprosartan does not have a biphenyl-methyl structure but in order to mimic the C-terminal end of Ang II the 5-acetic acid group was replaced with an a-thienylacrylic acid and a 4-carboxy-moiety. Eprosartan is a selective, potent and competitive AT antagonist and its binding to AT receptors is rapid, reversible, saturable and of high affinity.