A New Series of Imidazolones: Highly Specific and Potent Nonpeptide AT1 Angiotensin II Receptor Antagonists

Article abstract of DOI:10.1021/jm00074a018

Starting from the structure of the novel nonpeptide AT₁ receptor antagonists DuP 753 (losartan), a new series of potent antagonists was designed.In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure.The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5.Like the imidazole series, the best substituents were the linear butyl chain in position 2 and the <2'-(tetrazol-5-yl)biphenylyl>methyl group in position 3.Antagonistic activity was assessed by the ability of the compounds to competively inhibit <125I>AII binding to the AT₁ subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings.The most active compounds had IC50 values in the nanomolar range.In conscious 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 intravenously and orally.This molecule is now undergoing clinical trials for the treatment of hypertension.