title: 2(1H)-quinolinones with cardiac stimulant activity. 2. Synthesis and biological activities of 6-(N-linked, five-membered heteroaryl) derivatives.
abstract: A series of 6-(N-linked, five-membered heteroaryl)-2(1H)-quinolinone derivatives was synthesized and evaluated for cardiotonic activity. Most compounds were prepared by sulfuric acid catalyzed cyclization of an N-(4-heteroarylphenyl)-3-ethoxypropenamide or by condensation of a 2-amino-5-heteroarylbenzaldehyde or -acetophenone derivative with the ylide derived from triethyl phosphonoacetate. In anesthetized dogs, 6-imidazol-1-yl-8-methyl-2(1H)-quinolinone (3; 25 micrograms/kg) produced a greater increase in cardiac contractility (percentage increase in dP/dt max) than alternative 6-(five-membered heteroaryl)-substituted analogues (4-8). Introduction of 4-methyl (10) or 2,4-dimethyl (13) substituents into the imidazole ring of 3 produced a marked increase in inotropic activity, and these compounds were some 10 and 5 times more potent than milrinone. Most of these quinolinones also displayed positive inotropic effects (decrease in QA interval) in conscious dogs after oral administration (0.0625-1 mg/kg) and in many cases (3, 5-7, 9, 11, 13, 16) there was little difference in activities at both the 1- and 3-h time points. Compound 13 (62.5, 125, 250 micrograms/kg po) demonstrated dose-related cardiac stimulant activity which, in contrast to milrinone, was maintained over the whole 7-h test period. No changes in heart rate were detected at any dose level and compounds 3, 9, 10, and 13 also displayed high selectivity for the stimulation of cardiac contractile force rather than heart rate in the Starling dog heart-lung preparation. Increases in dP/dt max of approximately 50% were accompanied by heart rate changes of less than 10 beats/minute. Physicochemical measurements gave a log P of 1.64 for 13 with pKa values of 7.13 +/- 0.04 and 11.5 +/- 0.2 for the imidazole and quinolinone moieties, respectively. X-ray structural analysis of 13 showed the imidazole and quinolinone rings at 52 degrees to one another in close agreement with the minimum-energy conformation (30 degrees) suggested by PCILO calculations. 6-(2,4-Dimethylimidazol-1-yl)-8-methyl-2-(1H)-quinolinone (13, UK-61,260) is currently undergoing phase II clinical evaluation in congestive heart failure patients.
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 S
authors.initials: DS
authors.lastname: Morris
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; D002316:Cardiotonic Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D008958:Models, Molecular; D015394:Molecular Structure; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D002316:Cardiotonic Agents; D015363:Quinolones