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

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Abstract
Parallel series of 2-[(2-amidoethyl)amino]-1-arylethanols and 1-[(2-amidoethyl)amino]-3-(aryloxy)-2-propanols were prepared and tested as .beta.-adrenoceptor stimulants on the heart and circulation of the dog. The corresponding 2-(alkylamino)-1-arylethanols and 3-(alkylamino)-1-(aryloxy)-2-propanols were 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 produced. ICI 118587, N-[2-[[2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]-4-morpholinecarboxamide, was selected for its high cardioselectivity and 50% agonist properties. This compound is under clinical evaluation as a cardiac stimulant [and for treatment of heart failure].