Starting from the structure of the novel nonpeptide AT1 receptor antagonist 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 1 and the [2'-(tetrazol-5-yl)biphenylyl]methyl group in position 3. Antagonistic activity was assessed by the ability of the compounds to competitively 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.

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A New Series of Imidazolones: Highly Specific and Potent Nonpeptide AT1 Angiotensin II Receptor Antagonists.-A series of novel dihydroimidazol-4-ones, e.g. (V)-(VII), is synthesized and tested in vivo for angiotensin II antagonism at the AT1 subtype receptor. The most active compounds found, i.e. (VI) and ( VII), show IC50 values in the lower nanomolar range. -(BERNHART, C. A.; PERREAUT, P. M.; FERRARI, B. P.; MUNEAUX, Y. A.; ASSENS, J.-L. A.; CLEMENT, J.; HAUDRICOURT, F.; MUNEAUX, C. F.; TAILLADES, J. E.; VIGNAL, M.-A.; GOUGAT, J.; GUIRAUDOU, P. R.; LACOUR, C. A.; ROCCON, A.; CAZAUBON, C. F.; BRELIERE, J.-C.; LE FUR, G.; NISATO, D.; J. Med. Chem. 36 (1993) 22, 3371-3380; Sanofi Rech., 34184 Montpellier, Fr.; EN)