EXP3174: The Major Active Metabolite of Losartan

Abstract

Angiotensin I1 is the most active endogenous peptide in the renin-angiotensin system (RAS). Angiotensin I1 plays important roles in the development and maintenance of hypertension by altering peripheral resistance, renal function, and cardiovascular structure. In the treatment of hypertension, pharmacologic blockade of the l2AS has been considered to be a useful therapeutic modality. The pharmacological inhibition of the RAS was first attempted in 197 1 with saralasin, a peptide antagonist of angiotensin I1 (45). This peptide was useful clinically, but its therapeutic utility was limited by the fact that it displayed partial agonist activity and was not orally bioavailable (1,4554). Angiotensin converting enzyme (ACE) inhibitors were subsequently developed and are now widely used in the treatment of hypertension. ACE was initially described for its catalytic properties on two vasoactive peptides, angiotensin I and bradykinin. ACE is a rather nonspecific exopeptidase, however, sequentially cleaving dipeptides from the -COOH terminus of polypeptides such as enkephalins and neurotensins. ACE can also act as an endopeptidase, releasing predominantly C-terminal tripeptides from some substrates such as substance P and des-Arg'-bradykinin. Although ACE is active against a large number of substrates in v i m , the enzyme is actually more selective in vivo. The most compelling evidence for cleavage in vivo by ACE exists for angiotensin I and bradykmin (8,25). ACE processes angiotensin I into the active octapeptide angiotensin I1 and degrades bradykinin into inactive peptides. Thus, ACE inhibitors cause kinin potentiation in addition to decreasing angiotensin II production ( 18,26,54,65,70). ACE inhibitors also have some side effects, such as dry cough and angioedema. Since angiotensin I1 is the most active peptide in the RAS, the most direct way to block the RAS is to antagonize angiotensin I1 at the level of its receptor. In 1980, Furukawa and colleagues found that an imidazole derivative had the ability to