N-3-Substituted Pyrimidones as Potent, Orally Active, AT1 Selective Angiotensin II Receptor Antagonists

Article abstract of DOI:10.1021/jm00024a008

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 AT₁ 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 SKandF 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.