title: 2(1H)-quinolinones with cardiac stimulant activity. 1. Synthesis and biological activities of (six-membered heteroaryl)-substituted derivatives.
abstract: 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.
authors.affiliation: Department of Discovery Biology, Pfizer Central Research, Sandwich, Kent, United Kingdom.
authors.forename: C T
authors.initials: CT
authors.lastname: Alabaster
authors.forename: A S
authors.initials: AS
authors.lastname: Bell
authors.forename: S F
authors.initials: SF
authors.lastname: Campbell
authors.forename: P
authors.initials: P
authors.lastname: Ellis
authors.forename: C G
authors.initials: CG
authors.lastname: Henderson
authors.forename: D A
authors.initials: DA
authors.lastname: Roberts
authors.forename: K S
authors.initials: KS
authors.lastname: Ruddock
authors.forename: G M
authors.initials: GM
authors.lastname: Samuels
authors.forename: M H
authors.initials: MH
authors.lastname: Stefaniak
mesh_terms: D000818:Animals; D004285:Dogs; D006321:Heart / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D015363:Quinolones / Q000138:chemical synthesis / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
chemical_list: D015363:Quinolones