Synthesis and biological activity of the four stereoisomers of 6-[4-[3-[[2-hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]-propionamido] phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, a combined vasodilator and beta-adrenoceptor antagonist.
6-[4-[3-[[2-Hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]propionamido] phenyl]- 5-methyl-4,5-dihydro-3(2H)-pyridazinone (3) consists of a mixture of four stereoisomers, i.e., two racemates, as a consequence of the two asymmetric centers contained in the structure. An approximately equimolar mixture of these two racemates exhibits a novel combination of vasodilation and beta-adrenergic antagonist activity. This paper describes the synthesis of each of the four possible stereoisomers of 3 and provides clear evidence for the different pharmacological profile of each of the stereoisomers. The RA,SB isomer 3a has an overall profile slightly better than the complete mixture; the other three isomers all show reduced activity as vasodilators and/or beta-adrenergic antagonists.
D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002415:Cats; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology
C054816:6-(4-(3-((2-hydroxy-3-(4-(2-(cyclopropylmethoxy)ethyl)phenoxy)propyl)amino)propionamido)phenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone; D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D011724:Pyridazines; D014665:Vasodilator Agents