Nonpeptide angiotensin II-receptor antagonists

The renin-angiotensin system (RAS) is known to play a very important role in cardiovascular diseases. The present state of the research on orally active nonpeptide angiotensin II (A II)-receptor antagonists and their pharmacological characterization will be reviewed. In the late 1970s, the first nonpeptide A II-receptor antagonists were discovered among some derivatives of imidazoleacetic acid, and this was followed by the development of losartan in 1989. TCV-116, synthesized in our laboratories, is a prodrug that is converted in vivo to the active form CV-11974. TCV-116 and CV-11974 were demonstrated to be effective antagonists for many A II-induced cardiovascular actions and are effective antihypertensive agents in several animal models of hypertension. TCV-116 also demonstrated secondary benefits in treating congestive heart failure (CHF), preventing stroke, delaying the progression of renal disease and preventing the intimal thickening of vascular injury in animal models. Clinical studies confirmed the efficacy of TCV-116 in the treatment of essential hypertension. The utility of A II antagonist may extend beyond that of hypertension and CHF, as suggested by the potential usefulness of ACE inhibitors in the treatment or prevention of many other cardiovascular diseases. The A II antagonists will help to determine the role of the RAS in the physiologic regulation and in the pathophysiology of various cardiovascular diseases.