title: Design and synthesis of a series of combined vasodilator/beta-adrenoceptor antagonists based on 6-arylpyridazinones.
abstract: A series of new 6-[4-[[(aryloxy)acyl]amino]phenyl]-4,5-dihydropyridazinones have been synthesized and evaluated as combined vasodilator/beta-adrenoceptor antagonists and potential antihypertensive agents. Many of the early compounds displayed an unacceptably high level of intrinsic sympathomimetic activity (ISA) and a relatively short duration of action. Disubstitution in the 2,3-positions or in the 4-position of the aryloxy ring gave compounds with low ISA levels and, in some instances, improved duration of action. All of the compounds were vasodilators, but the 5-methylpyridazinone derivatives showed consistently greater antihypertensive activity than their 5-H lower homologues. Further detailed pharmacological investigations led to the selection of 6-[4-[3-[[2-hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]propionamido] phenyl]- 5-methyl-4,5-dihydro-3(2H)-pyridazinone (4t) (SK&F 95018) as a development candidate.
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002415:Cats; D005260:Female; D008297:Male; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013566:Sympathomimetics / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D011724:Pyridazines; D013566:Sympathomimetics; D014665:Vasodilator Agents