Renal vasodilators. The role of the 4-substituent in isoquinolin-3-ol cardiovascular agents. 4-Ureido derivatives of isoquinolin-3-ol with selective renal vasodilator properties

• Published in: Journal of medicinal chemistry Vol. 32; no. 5; pp. 990 - 997
• Main Authors: Kanojia, Ramesh M, Lever, O. William, Press, Jeffery B, Williams, Louella, Werblood, Harvey M, Giardino, Edward C, Falotico, Robert, Tobia, Alfonso J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-05-1989
• Subjects: Animals; blood pressure; Blood Pressure - drug effects; Chemistry; chronotropism; Dogs; Exact sciences and technology; Heart Rate - drug effects; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Isoquinolines - pharmacology; Organic chemistry; Preparations and properties; Renal Circulation - drug effects; Structure-Activity Relationship; Vascular Resistance - drug effects; Vasodilator Agents - chemical synthesis; Vasodilator Agents - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00125a011

The synthesis and cardiovascular evaluation of a series of isoquinolin-3-ol derivatives bearing a variety of nitrogen substituents (amino, acylamino, carbamate, and ureido) at C-4 are described. Certain of these compounds have a selective renal vasodilating profile and have minimal effects on arterial blood pressure or heart rate when administered intravenously in the instrumented anesthetized dog. The most potent renal vasodilator in the series is 4-(allylureido)-6,7-dimethoxyisoquinolin-3-ol (38), which at a dose of 1.2 mg/kg iv produces a 97% maximal increase in renal blood flow without significant hypotensive or chronotropic effects. Structure-activity observations on the nature of the 4-substituent and the alkoxy substitution pattern in the aromatic ring of the isoquinolinol nucleus are discussed.