Description
Milrinone is an inhibitor of type 3 phosphodiesterases (PDEs), inhibiting recombinant PDE3A and PDE3B with IC
50 values of 0.45 and 1 μM, respectively.
1 It is selective for PDE3 over PDE1, PDE2, PDE4, PDE5, and PDE7 (IC
50s = 263, >300, 17.5, 49.1, and 58.3 μM, respectively).
1 Milrinone (0.1-1 mg/kg) has positive inotropic effects, increasing cardiac contractile force in anesthetized dogs with a concomitant increase in heart rate but not blood pressure.
2 It also increases contractile force in models of propranolol- and verapamil-induced heart failure in anesthetized dogs when administered at an initial dose of 30 μg/kg followed by a continuous 3 μg/kg per minute infusion. Milrinone has vasodilatory effects as well, decreasing mean aortic pressure and increasing venous compliance in anesthetized dogs when administered at an initial dose of 10 μg/kg followed by a continuous 1.7-2.4 μg/kg per minute infusion.
3 Formulations containing milrinone have been used in the treatment of heart failure.
Description
Milrinone, an inhibitor of phosphodiesterase selective for fraction III PDE, exerts a
positive inotropic effect on the heart as well as a peripheral vasodilatory effect. Milrinone
given intravenously produces significant improvements on cardiac output, pulmonary
capillary wedge pressure and vascular resistance without significant effects on the heart
rate.
Originator
Eastman Kodak (Sterling) (USA)
Definition
ChEBI: Milrinone is a member of the class of bipyridines that is 2-pyridone which is substituted at positions 3, 5, and 6 by cyano, pyrid-4-yl, and methyl groups, respectively. It is used (particularly intravenously, as the lactate) for the short-term management of severe heart failure. It has a role as an EC 3.1.4.17 (3',5'-cyclic-nucleotide phosphodiesterase) inhibitor, a platelet aggregation inhibitor, a vasodilator agent and a cardiotonic drug. It is a pyridone, a nitrile and a member of bipyridines.
Manufacturing Process
A mixture containing 20 g of 1-(4-pyridinyl)-2-propanone and 30 ml ofhexamethylphosphoramide was diluted with 65 ml of dimethylformamidedimethyl acetal and the resulting mixture was refluxed for 30 min. TLCanalysis showed a single spot, thereby indicating completion of the reaction(in another run, the reaction appeared to be complete after 30 min at roomtemperature). The mixture was evaporated under reduced pressure and apressure, thereby resulting in a crystalline residue weighing 24 g. The residuewas purified by continuous chromatographic extraction on alumina (about 150g) using refluxing chloroform as eluant. After 90 min, the extract was heatedin vacuo to remove the chloroform, thereby leaving, as a light yellowcrystalline material, 23.2 g of 1-(4-pyridinyl)-2-(dimethylamino)ethenylmethyl ketone, alternatively named 4-dimethylamino-2-(4-pyridinyl)-3-buten-2-one.
To a mixture containing 23 g of 1-(4-pyridinyl)-2-(dimethylamino)ethenylmethyl ketone and 11 g of α-cyanoacetamide dissolved in 400 ml ofdimethylformamide was added with stirring 14 g of sodium methoxide and theresulting reaction mixture was heated in an oil bath under gentle reflux forone hour. TLC analysis showed no starting material in the reaction mixturewhich was then concentrated in vacuo on a rotary evaporator to a volume ofabout 80 ml. The concentrate was treated with about 160 ml of acetonitrileand the resulting mixture was stirred on a rotary evaporator with warminguntil homogenous and then cooled. The crystalline product was collected,rinsed successively with acetonitrile and ether, and dried overnight at 55°C toyield 28 g of crystalline product, namely, sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of cyano being confirmed byIR analysis. An 8 g portion of said sodium salt was dissolved in 75 ml of hotwater, the aqueous solution treated with decolorizing charcoal, filtered, thefiltrate again treated with decolorizing charcoal and filtered, and the filtrateacidified with 6 N hydrochloric acid by dropwise addition to a pH of 3. Theacidic mixture was diluted with ethanol and cooled. The crystalline productwas collected, dried, recrystallized from dimethylformamide-water and dried toproduce 3.75 g of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile,m.p. >300°C.
Another method of preparation of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile (Patent US 4,413,127)
A 69.5 g portion of 1-ethoxy-2-(4-pyridinyl)ethenyl methyl ketone wasdissolved in 300 ml of ethanol and to the solution was added 13.2 g ofmalononitrile. The resulting mixture was refluxed for 5 hours, crystals startingto separate after about 30 min of refluxing. The reaction mixture was allowedto cool to room temperature and, the precipitate of fine needles was filtered,washed with ethanol and dried in a vacuum at 90°C to yield 25.4 g of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)-nicotinonitrile, m.p. >300°C.Concentration of the mother liquor provided another 2.1 g of product, m.p.>300°C.
To a aqueous solution of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile was added one molar equivalent of lactic acid to prepare themonolactate of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.
Brand name
Primacor (Sterling Winthrop);Corotrope.
Therapeutic Function
Cardiotonic
General Description
Milrinone, 1,6-dihydro-2-methyl-6-oxo-3,4＇-bipyridine-5-carbonitrile (Primacor), is another dipyridinephosphodiesterase F-III inhibitor that possesses pharmacologicalproperties similar to those of amrinone. The inhibitionof the degradation of cAMP results in an increase in the cardiacmuscle’s force of contraction.
Biological Activity
Potent cAMP phosphodiesterase inhibitor (IC 50 = 56 nM for inhibition of PDE III). Has inotropic and vasodilator effects following oral or intravenous administration in vivo . Also available as part of the Phosphodiesterase Inhibitor Tocriset™ .
Biochem/physiol Actions
Phosphodiesterase type III inhibitor; cAMP-specific, cGMP-inhibitable; potent cardiotonic, positive inotropic vasodilator.
References
[1] tang km1, jang ek, haslam rj. photoaffinity labelling of cyclic gmp-inhibited phosphodiesterase (pde iii) in human and rat platelets and rat tissues: effects of phosphodiesterase inhibitors. eur j pharmacol. 1994 jun 15;268(1):105-14.
[2] cheung p1, yang g, boden g. milrinone, a selective phosphodiesterase 3 inhibitor, stimulates lipolysis, endogenous glucose production, and insulin secretion. metabolism. 2003 nov;52(11):1496-500.
