4-(Heteroarylthio)-2-biphenylyltetrazoles as Nonpeptide Angiotensin II Antagonists

• Published in: Journal of medicinal chemistry 1995-11, Vol.38 (23), p.4670-4678
• Main Authors: Norman, Mark H, Smith, H. David, Andrews, C. Webster, Tang, Flora L. M, Cowan, Conrad L, Steffen, Robert P
• Format: Article
• Language: English
• Subjects: Angiotensin II - antagonists & inhibitors; Angiotensin II - metabolism; Angiotensin II - pharmacology; Angiotensin Receptor Antagonists; Animals; Aorta, Abdominal - drug effects; Aorta, Abdominal - physiology; Binding, Competitive; Biological and medical sciences; Biphenyl Compounds - pharmacology; Cardiovascular system; Imidazoles - pharmacology; Losartan; Male; Medical sciences; Models, Molecular; Muscle Contraction - drug effects; Naphthyridines - chemical synthesis; Naphthyridines - metabolism; Naphthyridines - pharmacology; Pharmacology. Drug treatments; Quinolines - chemical synthesis; Quinolines - metabolism; Quinolines - pharmacology; Rabbits; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Angiotensin - metabolism; Saralasin - pharmacology; Structure-Activity Relationship; Sulfides - chemistry; Tetrazoles - chemical synthesis; Tetrazoles - metabolism; Tetrazoles - pharmacology; Vasodilator agents. Cerebral vasodilators
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00023a006

A series of 4-(heteroarylthio)-2-biphenylyltetrazoles was prepared, and the compounds were examined for their ability to displace [3H]AII from angiotensin II receptors. Analogues that exhibited significant receptor binding affinities at less than 10 microM were investigated further for potential antagonism of angiotensin II-mediated contraction of rabbit isolated aortic rings. Three 4-(heteroarylthio)-2-biphenylyltetrazoles were identified that exhibited sub-micromolar angiotensin II receptor binding affinities. These compounds and two reference agents, saralasin and losartan (DUP-753), exhibited concentration-dependent reversal 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-biphenylyltetrazoles. The biological effects of the sulfide bridge as well as alterations in the heteroaromatic moiety were investigated, and the resulting structure--activity relationships are discussed.