RESUMEN
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.
Asunto(s)
Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Imidazoles/síntesis química , Imidazoles/farmacología , Animales , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Femenino , Técnicas In Vitro , Irbesartán , Macaca fascicularis , Masculino , Conejos , Ratas , Ratas Sprague-Dawley , Receptores de Angiotensina/metabolismo , Sensibilidad y Especificidad , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/farmacologíaRESUMEN
Free-Wilson and correlation analysis were combined to study a series of 34 pepstatin analogues in which mainly position 2 was varied. A statistically highly significant correlation was found between the inhibitory activity of the analogues on an enriched plasma renin preparation and structural parameters of the amino acid side chain in position 2. The crucial parameters were found to be the NMR chemical shift of the alpha-carbon, the localized electrical (inductive) effect, and the van der Waals radius related steric parameter, which demonstrated the dominating influence of electronic inductive effects compared to steric bulk. The model gives insight into the structural requirements for effective inhibition and suggests the histidine-2 derivative, a positive outlier in this series, as a lead compound for further structure-activity studies.
