Synthesis and cardioselective beta-adrenergic antagonist activity of quinolyloxypropanolamines.
The synthesis and beta-adrenergic antagonist activities of (2R,2S)-, (2S)-, (2R)-1-(5-quinolyloxy)-3-alkylamino-2-propanols (10-21) and (2R,2S)-1-(5-isoquinolyloxy)-3-alkylamino-2-propanols (24-27) is described. beta 1-Adrenolytic (atria) structure-activity correlations indicated the N-alkyl substituent was a determinant of activity where the relative potency order was i-Pr and t-Bu > cyclohexyl. Compounds having the (2S)-configuration were more potent than the corresponding (2R)-analogs. The position of the heteroaryl nitrogen atom influences potency since the quinolyl analogs were ten-fold more active than the corresponding isoquinolyl isomers. All compounds in both the quinolyl and isoquinolyl series exhibited weak beta 2-adrenolytic activity (trachea), and high beta 1/beta 2 selectivity ratios when the N-alkyl substituent was i-Pr or t-Bu. The quinolyl ring system is an excellent bioisostere for the aryl moiety in aryloxypropanolamines since (2R,2S)- or (2S)-1-(5-quinolyloxy)-3-isopropyl (or t-Bu) amino-2-propanols exhibit very potent and highly cardioselective beta 1-adrenergic antagonist activities.
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Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Wolowyk
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Knaus
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D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D009130:Muscle, Smooth / Q000187:drug effects; D011412:Propanolamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D011804:Quinolines