POTENT AND ORALLY-ACTIVE ANGIOTENSIN-II RECEPTOR ANTAGONISTS WITH EQUAL AFFINITY FOR HUMAN AT(1) AND AT(2) SUBTYPES

In order to block the effects induced by the interactions between angi otensin II (AII) and both AT(1) and AT(2) receptors, we have pursued t he discovery of orally active non-peptide AII antagonists that exhibit potent and equal affinity for human AT(1) and AT(2) receptor subtypes . A series of previously prepared nanomolar (IC50) trisubstituted 1,2, 4-triazolinone biphenyl-sulfonamide dual-acting AII antagonists has be en modified at five different positions in order to increase AT(2) bin ding affinity, maintain AT(1) activity, and reduce the human adrenal A T(2)/AT(1) potency ratio (IC50 ratio) from greater than or equal to 10 . The targeted human adrenal potency ratio of less than or equal to 1 was achieved with a number of compounds possessing an ethyl group at C -5 of the triazolinone and a 3-fluoro substituent at the N-4-biarylmet hyl moiety. The most favored of these was compound 44 which exhibited subnanomolar potency at both the AT(1) (rabbit aorta) and AT(2) (rat m idbrain) receptors, with a slight preference for the latter, and had a human adrenal AT(2)/AT(1) IC50 ratio of 1. This tert-butyl sulfonylca rbamate with an N-2-[2-bromo-5-(valerylamino)phenyl] substituent had e xcellent iv activity at 1 mg/kg (100% peak inhibition, greater than or equal to 4 h duration of action) and is orally active at 3 mg/kg with >6 h duration of action in a conscious rat model. The present study s hows that the NH of the amide on the N-2-aryl moiety is not required f or subnanomolar binding affinity to either receptor subtype, although a keto functionality at this position is essential for acceptable AT(2 ) binding. Receptor-ligand binding interactions derived from the struc ture-activity relationships are discussed with respect to both recepto r subtypes.