ANGIOTENSIN RECEPTOR ANTAGONISTS act principally at the AT1 and/or AT2 receptors (see ANGIOTENSIN receptor AGONISTS). The first antagonists were derived in the early 1970s by substitutions within the angiotensin sequence. Saralasin ((Sar1,Ala8]-AII) blocks at both AT, and AT2 receptors, and is quite active experimentally, but is not stable in the body and was not used clinically. The first nonpeptide antagonists, announced in the early 1980s, were imidazole-5-acetic acid derivatives (e.g. S 8307 and S 8308), and acted as lead compounds from which stepwise modifications (through EXP 6155. EXP 6803, EXP 7711) led to orally active agents. The first of these registered for clinical usage (in 1995 in the UK and USA) was losartan, which can be used as an ANTIHYPERTENSIVE. This, and several other nonpeptide antagonists under clinical development, are more active at AT, receptors. Examples include candesartan, eprosartan, irbesartan, telmisartan. valsartan and zolasartan.

There is currently little incentive to develop drugs that work by blocking angiotensin AT2 receptors since the role of these in body function is not clear. Nevertheless, there are experimental agents that act at both receptors (e.g. saralasin and others that are selective for the AT2 subtype (e.g. PD 123319 and PD 123177).

The use of angiotensin receptor antagonists to treat hypertension is an obvious application. In fact, losartan also has a significant uricosuric effect with a decrease in plasma levels of uric acid that, in principle, could be harnessed therapeutically (e.g. in the treatment of gout). Also, there are trials in progress for its actions in left ventricular dysfunction and progressive renal impairment. One advantage of angiotensin receptor antagonists over ACE inhibitors seems to be an absence of propensity for causing an irritating cough. There may be future roles in modifying CNS function.