Linked Life Data

2845085

Source:http://linkedlifedata.com/resource/pubmed/id/2845085

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
1988-11-18
pubmed:abstractText
A series of (six-membered heteroaryl)-substituted 2(1H)-quinolinones (1) was synthesized, and structure-activity relationships for cardiac stimulant activity were determined. Most compounds were prepared by acidic hydrolysis of a heteroaryl-2-methoxyquinoline obtained by palladium-catalyzed cross-coupling methodology. Direct reaction of a pyridinylzinc reagent with a 6-haloquinolinone also proved successful. In anesthetized dogs, 6-pyridin-3-yl-2(1H)-quinolinone (3; 50 micrograms/kg) displayed greater inotropic activity (percentage increase in dP/dt max) than positional isomers (2, 4-6), and potency was maintained with either mono- (13, 15) or di- (16) alkylpyridinyl substituents. Introduction of a 4- (24) or 7- (25) methyl group into 3 reduced inotropic activity, whereas the 8-isomer (26) proved to be the most potent member of the series. Compound 26 and the 2,6-dimethylpyridinyl analogue (27) were approximately 6 and 3 times more potent than milrinone. Several quinolinones displayed positive inotropic activity (decrease in QA interval) in conscious dogs after oral administration (1 mg/kg), and 26, 27 were again the most potent members of the series. Compound 27 (0.25, 0.5, 1.0 mg/kg po) demonstrated dose-related cardiac stimulant activity, which was maintained for at least 4 h. No changes in heart rate were observed. Compounds 3, 4, 26, and 27 also selectively stimulated the force of contraction, rather than heart rate, in the dog heart-lung preparation. For a 50% increase in dP/dt max with 27, heart rate changed by less than 10 beats/min. In norepinephrine contracted rabbit femoral artery and saphenous vein, 27 produced dose related (5 X 10(-7) to 5 X 10(-4) M) vasorelaxant activity. The combined cardiac stimulant and vasodilator properties displayed by 27, coupled with a lack of effect on heart rate, should be beneficial for the treatment of congestive heart failure.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:volume
31
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2048-56
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed:year
1988
pubmed:articleTitle
2(1H)-quinolinones with cardiac stimulant activity. 1. Synthesis and biological activities of (six-membered heteroaryl)-substituted derivatives.
pubmed:affiliation
Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent, United Kingdom.
pubmed:publicationType
Journal Article