beta.-Adrenoceptor stimulant properties of amidoalkylamino-substituted 1-aryl-2-ethanols and 1-(aryloxy)-2-propanols

• Published in: Journal of medicinal chemistry Vol. 24; no. 3; pp. 315 - 322
• Main Authors: Barlow, Jeffrey J, Main, Brian G, Snow, H. Michael
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.03.1981
• Subjects: Adrenergic beta-Agonists - chemical synthesis; Adrenergic beta-Agonists - pharmacology; Animals; Dogs; Ethanolamines - chemical synthesis; Ethanolamines - pharmacology; Heart Rate - drug effects; Propanolamines - chemical synthesis; Propanolamines - pharmacology; Receptors, Adrenergic, beta - drug effects; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00135a015

Parallel series of 2-[(2-amidoethyl)amino]-1-arylethanols and 1-[(2-amidoethyl)amino]-3-(aryloxy)-2-propanols have been prepared, and the compounds were tested as beta-adrenoceptor stimulants on the heart and circulation of the dog. The corresponding 2-(alkylamino)-1-arylethanols and 3-(alkylamino)-2-propanols have been tested for comparison and the structure-activity relationships (SAR) examined. The arylethanols are potent full agonists, showing selectivity for the heart relative to blood vessels, while the (aryloxy)propanols are even more cardioselective and are partial agonists. Within a narrow series of 1-[(amidoethyl)amino]-3-(4-hydroxyphenoxy)-2-propanols, careful examination of the SAR of the amide group showed that great variation in cardioselectivity and degree of agonism may be produce. From this study ICI 118587, N-[20[[2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]-4-morpholinecarboxamide, was selected for its high cardioselectivity and 50% agonist properties. This compound in under clinical evaluation as a cardiac stimulant.