N-3-substituted pyrimidinones as potent, orally active, AT1 selective angiotensin II receptor antagonists
| Autor: | A, Salimbeni, R, Canevotti, F, Paleari, D, Poma, S, Caliari, F, Fici, R, Cirillo, A R, Renzetti, A, Subissi, L, Belvisi |
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| Rok vydání: | 1995 |
| Předmět: |
Male
Models Molecular Stereochemistry Molecular Conformation Administration Oral Pyrimidinones Thiophenes Chemical synthesis Rats Sprague-Dawley Angiotensin Receptor Antagonists Structure-Activity Relationship Oral administration In vivo Drug Discovery Moiety Animals Humans Angiotensin II receptor type 1 Molecular Structure Chemistry Angiotensin II Rats Hypertension Molecular Medicine Pharmacophore |
| Zdroj: | Journal of medicinal chemistry. 38(24) |
| ISSN: | 0022-2623 |
| Popis: | A novel series of nonpeptide angiotensin II (A II) antagonists containing a pyrimidinone ring which carries a C-linked biphenyltetrazole moiety and a carboxyheteroaryl group on the 3-position have been prepared. Their affinity for the AT 1 receptor was determined in a binding assay on rat adrenal cortical membranes. The in vivo antihypertensive properties were tested by evaluating the inhibition of the pressor response to A II followed by iv and id administration. Extensive molecular modeling studies, including comparison of molecular electrostatic potential distributions, conformational analysis, and overlays on a computational pharmacophore model of A II, were used to evaluate structural parameters of the new compounds, in comparison to other known A II antagonists (e.g., DUP-753 and SK&F 108566). According to the modeling studies, the introduction of a (carboxyheteroaryl)methyl moiety at the 3-position of the pyrimidinone ring led to derivatives with increased potency. Methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1-(6H)-pyrimidinyl]methyl]-3-thiophenecarboxylate (3k, LR-B/081), one of the most potent compounds in the series (K i = 1.4 nM), exhibited a marked antihypertensive activity on oral administration to conscious renal hypertensive rats, with long duration of action. It was selected for clinical evaluation in the treatment of hypertension in man. |
| Databáze: | OpenAIRE |
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