N-3-SUBSTITUTED PYRIMIDINONES AS POTENT, ORALLY-ACTIVE, AT(1) SELECTIVE ANGIOTENSIN-II RECEPTOR ANTAGONISTS

A novel series of nonpeptide angiotensin II (A II) antagonists contain ing a pyrimidinone ring which carries a C-linked biphenyltetrazole moi ety and a carboxyheteroaryl group on the 3-position have been prepared . Their affinity for the AT(1) receptor was determined in a binding as say on rat adrenal cortical membranes. The in vivo antihypertensive pr operties were tested by evaluating the inhibition of the presser respo nse to A II followed by iv and id administration. Extensive molecular modeling studies, including comparison of molecular electrostatic pote ntial distributions, conformational analysis, and overlays on a comput ational pharmacophore model of A II, were used to evaluate structural parameters of the new compounds, in comparison to other known A II ant agonists (e.g., DUP-753 and SK&F 108566). According to the modeling st udies, the introduction of a (carboxyheteroaryl)methyl moiety at the 3 -position of the pyrimidinone ring led to derivatives with increased p otency. Methyl -1-(6H)-pyrimidinyl]methyl]-3-thiophenecarboxylate (3k, LR-B/081), one oft he most potent compounds in the series (K-i = 1.4 nM), exhibited a marked antihypertensive activity on oral administrati on to conscious renal hypertensive rats, with long duration of action. It was selected for clinical evaluation in the treatment-of hypertens ion in man.