151257-04-4Relevant articles and documents
A New Series of Imidazolones: Highly Specific and Potent Nonpeptide AT1 Angiotensin II Receptor Antagonists
Bernhart, Claude A.,Perreaut, Pierre M.,Ferrari, Bernard P.,Muneaux, Yvette A.,Assens, Jean-Louis A.,et al.
, p. 3371 - 3380 (2007/10/02)
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 methyl group in position 3.Antagonistic activity was assessed by the ability of the compounds to competively inhibit 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.
