The renin-angiotensin system (RAS) is recognized as a key element in blood pressure regulation and electrolyte/fluid homeostasis.1 As outlined in Figure 1, the RAS constitutes a proteolytic cascade in which angiotensinogen from the liver is cleaved by the aspartyl protease renin to produce the decapeptide angiotensin I (Ang I). Biologically inactive Ang I is cleaved by the metalloprotease angiotensin-converting enzyme (ACE) to produce the endogenous octapeptide hormone angiotensin II (Ang II). The clinical and commercial success of ACE inhibitors2 such as captopril3 and enalapril4 for the treatment of hypertension and congestive heart failure has initiated substantial interest in the exploration of novel ways to interfere with the RAS cascade.5,6 Despite the fact that ACE inhibitors have met with a high degree of success, ACE is a nonspecific protease which is also responsible for the degradation of bradykinin as well as other peptides such as substance P and enkephalins.7 The dry cough that occurs in 5-10% of the population treated with ACE inhibitors and the rare instances of angioedema have been proposed to be the result of the lack of specificity of ACE; more specifically these side effects have been attributed to bradykinin potentiation.8 In the search for novel methods of intervention, inhibitors of renin have also been extensively investigated. However, to date, poor oral bioavailability, rapid biliary excretion, and the structural complexity of most renin inhibitors have hampered their development as drugs.9 While progress has been made toward eliminating these liabilities, the pharmaceutical industry has been unsuccessful in bringing a renin inhibitor to market. Inhibition of the terminal step in the RAS, i.e., Ang II receptor blockade, offers a highly specific approach to inhibition of the system regardless of the source of Ang II. Also, since ACE would not be affected by such agents, potentiation of bradykinin and hence cough or angioedema by this mechanism would not be expected during therapy with an Ang II blocker.10 Although potent peptide Ang II receptor antagonists such as Phe4-Tyr8-Ang II and saralasin (Sar1-Ala8-Ang II) have been used as pharmacological tools for the past 2-3 decades, these peptides have limited therapeutic value because of their poor oral bioavailability, short duration of action, and significant agonist properties.11,12 The concept that nonpeptide Ang II antagonists would lack the disadvantages of the peptide Ang II receptor antagonists was an attractive but elusive strategy until 1982, when Furukawa and co-workers at Takeda Chemical Industries disclosed a series of 1-benzylimidazole-5-acetic acid derivatives.13,14 In these early patent publications, several compounds from this series were reported to inhibit the Ang II-induced contractile response in rabbit aorta and the pressor response in the Ang II-infused rat, but no information was given on the selectivity of these compounds. Two compounds from the Takeda series, S-8307 (CV2947) and S-8308 (CV2961), were prepared and studied thoroughly by the DuPont group and confirmed to be weak but selective competitive Ang II receptor antagonists lacking agonist properties.15,16 These early compounds demonstrated the feasibility of nonpeptide Ang II receptor antagonists and served as the starting point which culminated in the discovery of losartan (COZAAR, also designated as DuP 753 and MK-954), which is the prototype of this new class of potent, orally active, nonpeptide Ang II receptor antagonists.17-19