A NEW SERIES OF IMIDAZOLONES - HIGHLY SPECIFIC AND POTENT NONPEPTIDE AT(1) ANGIOTENSIN-II RECEPTOR ANTAGONISTS

Starting from the structure of the novel nonpeptide AT1 receptor antag onist DuP 753 (losartan), a new series of potent antagonists was desig ned. In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure. The most active compounds had a s pirocyclopentane or a spirocyclohexane ring in position 5. Like the im idazole series, the best substituents were the linear butyl chain in p osition 2 and the [2'-(tetrazol-5-yl)biphenylyl]methyl group in positi on 3. Antagonistic activity was assessed by the ability of the compoun ds to competively inhibit [I-125]AII binding to the AT1 subtype recept or and to antagonize AII-induced contractions in rabbit aorta rings. T he most active compounds had IC50 values in the nanomolar range. In co nscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally. Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both int ravenously and orally. This molecule is now undergoing clinical trials for the treatment of hypertension.