NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS

The renin-angiotensin system (RAS) plays an important role in blood pressure regulation and electrolyte homeostasis. Angiotensin II (AII) is the principal active hormone of this system and blockade of the action of AII has been a target for development of novel antihypertensive agents. In the latter half of 1970's, imidazoleacetic acid derivatives were synthesized and discovered to be the first nonpeptide AII antagonists. Structure-activity relationship study of these compounds revealed that CV-2961 (17) had fairly strong AII receptor antagonistic activity. This finding prompted many researchers to develop more potent AII antagonists and led to the discovery of DuP 753 (Losartan) by Du Pont. Further investigation on various heterocycles related to imidazole culminated in the creation of novel diacidic benzimidazole derivatives, CV-11194 (34) and 11974(Candesartan : 36). A series of ester prodrugs of these compounds was prepared in attempt to improve oral bioavailability. One of the prodrugs thus obtained, TCV-116 (1 : Candesartan cilexetil) showed orally active, highly potent and]longlasting antihypertensive effect in several hypertensive animal models and is under clinical trials. The history of these researches, especially chemical aspect, will be presented.