title: Novel positive inotropic agents: synthesis and biological activities of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolinone derivatives.
abstract: A series of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolinones has been synthesized and evaluated for positive inotropic activity on the canine heart. Some of these derivatives have a potent activity with none or negative chronotropic effect in isolated, blood-perfused dog heart preparations. They also display a high selectivity for positive inotropic effect over chronotropic and vasodilatory effects in anesthetized dogs. (+/-)-6-[2-Hydroxy-3-[(3-methoxybenzyl)amino]propoxy]-2(1H)-quinolinone (39) and (+/-)-6-[3-(3,4-dimethoxybenzyl)amino]-2-hydroxypropoxy]-2 (1H)-quinolinone (40) were further investigated in conscious dogs. After iv administration, they did not affect heart rate or mean blood pressure at the dose producing a 50% increase in the peak of the first derivative of the left ventricular pressure. The compounds (39, OPC-18750, and 40, OPC-18790) are the most promising agents with desirable biological activities, and now are currently undergoing clinical evaluation.
authors.affiliation: 2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Company, Ltd., Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fujioka
authors.forename: S
authors.initials: S
authors.lastname: Teramoto
authors.forename: T
authors.initials: T
authors.lastname: Mori
authors.forename: T
authors.initials: T
authors.lastname: Hosokawa
authors.forename: T
authors.initials: T
authors.lastname: Sumida
authors.forename: M
authors.initials: M
authors.lastname: Tominaga
authors.forename: Y
authors.initials: Y
authors.lastname: Yabuuchi
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D002316:Cardiotonic Agents; D015363:Quinolones; C078152:OPC 18750; C077543:toborinone