4-(HETEROARYLTHIO)-2-BIPHENYLYLTETRAZOLES AS NONPEPTIDE ANGIOTENSIN-II ANTAGONISTS

A series of 4-(heteroarylthio)-2-biphenylyltetrazoles was prep are d, and the compounds were examined for their ability to displace [H-3]AII from angiotensin II receptors. Analogues that exhibited significant r eceptor binding affinities at less than 10 mu M were investigated furt her for potential antagonism of angiotensin II-mediated contraction of rabbit isolated aortic rings. Three 4-(heteroarylthio)-2-biphenylylte trazole were identified that exhibited sub-micromolar angiotensin II r eceptor binding affinities. These compounds and two reference agents, saralasin and losartan (DUP-753), exhibited concentration-dependent re versal of angiotensin II contraction in isolated aortic rings parallel to their receptor binding affinities. Molecular modeling studies were conducted to examine the conformational effects of the novel sulfide bridging unit contained in these 4-(heteroarylthio)-2-biphenylyltetraz oles. The biological effects of the sulfide bridge as well as alterati ons in the heteroaromatic moiety were investigated, and the resulting structure-activity relationships are discussed.