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.