The aminoquinazoline group as a replacement for the salicylamide group: the design and synthesis of a novel highly selective beta 1 adrenoceptor partial agonist.
The high potency at beta 1 receptors, excellent selectivity (beta 1/beta 2) and high degree of agonism displayed by compounds such as 1 is believed to be due in part to the salicylamide side chain. Two conformations of salicylamide are known to exist in the crystal state (2 and 3), but ab initio calculations suggest that in the absence of crystal packing forces 2 should be more stable. The aminoquinazoline group was judged to be a good replacement for salicylamide in 1, and consequently the oxypropanolamine derivative 4 was prepared. 4 shows extremely high potency at the beta 1 receptor, and excellent beta 1/beta 2 selectivity. It has comparable in vitro activity to 1, although it displays a lower degree of agonism. These results suggest that in this system aminoquinazoline appears to be an excellent mimic of the salicylamide group.
ICI Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, England.
M H
MH
Block
P W
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Kenny
D S
DS
Thomson
M T
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Yu
D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D015195:Drug Design; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D011169:Portal Vein / Q000187:drug effects; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D012457:Salicylamides / Q000737:chemistry* / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D011799:Quinazolines; D012457:Salicylamides