Pyridazinone Hydrochloride Research Articles

Study on pyridazinone derivative MCI-154 as a cardiotonic agent

The effect of a cardiotonic agent, MCI-154, 6-[4-(4’-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate, is a Ca2+ sensitizer on the contractile properties and adenosine triphosphatase ATPase activity on skeletal muscle fibers. As in cardiac m uscle, MCI-154 potentiated isometric tension and improved isometric tension cost at full Ca2+ activation. However, MCI-154 decreased all the kinetic parameters. The MCI-154 improves not only cardiac systolic function but also diastolic relaxation in CHF. The possible mechanisms are Ca2+ transient and cell shortening in ventricular myocytes and also L-type Ca2+ current and Na+/Ca2+ exchange current. The MCI-154 exhibited hemodynamic, inotropic, mechano-energetic and oxidative metabolic effects.

Effects of MCI-154 on Vascular Reactivity and Its Mechanisms After Hemorrhagic Shock in Rats

The objectives of this study were to investigate the effects of 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate (MCI-154), a newly developed cardiotonic agent, on vascular reactivity and contractile responses to extracellular Ca2+ ([Ca2+]o) after hemorrhagic shock and primarily explore its mechanism. In vivo, the effects of MCI-154 (0.1, 0.5, 1.0, and 2.0 mg/kg) on the pressor effect of norepinephrine (NE) in rats subjected to hemorrhagic shock (30 mm Hg for 2 h) were observed and in vitro, the effects of MCI-154 (10(-7), 10(-6), 10(-5), 10(-4) mol/L) on vascular reactivity and contractile responses to [Ca2+]o of superior mesenteric artery (SMA) from hemorrhagic shock rats and its relationship to Rho-kinase, protein kinase C (PKC), and protein kinase G (PKG) were observed. The results showed that the NE-induced pressor response after hemorrhagic shock was significantly decreased (P<0.01), and MCI-154 made it decrease further. In vitro, MCI-154 further decreased the contractile responses of SMA to NE and Ca2+ after hemorrhagic shock as compared with untreated hemorrhagic shock group (P<0.01). Angiotensin II (Ang II), with Rho-kinase stimulating action, and PMA, a PKC agonist increased the contractile responses to [Ca2+]o of SMA after hemorrhagic shock. MCI-154 (10(-5) mol/L) partly inhibited Ang II and PMA-induced increase of the contractile responses to [Ca2+]o of SMA (P<0.01). KT-5823, the PKG antagonist, antagonized MCI-154-induced decrease of the contractile responses to [Ca2+]o. Taken together, these results suggested that the vascular reactivity and contractile responses to [Ca2+]o of vascular smooth muscle after hemorrhagic shock were significantly decreased. MCI-154 worsened hemorrhagic shock-induced vascular hyporeactivity and the decrease of contractile responses to [Ca2+]o. These effects were possibly regulated by Rho-kinase, PKC, and PKG, but this needs further confirmation.

Two Stage Solid Phase Extraction with Subsequent HPLC Isolation for Structure Elucidation of Major Metabolites of (+)-(R)-2-{3-(benzo[1,4]dioxan-2-yl-methylamino)-1-propyl}-3(2H)-pyridazinone (GYKI-16084)

GYKI-16084 – (+)-(R)-2-{3-(benzo[1,4]dioxan-2-yl-methylamino)-1-propyl}-3(2H)-pyridazinone hydrochloride – is a new drug candidate for the treatment of benign prostatic hyperplasia. In our study the major metabolites formed in the rat and dog were isolated from dog and rat urine, then their structures were elucidated by means of MS and NMR. A two stage solid phase extraction (SPE) procedure and a semi-preparative HPLC method were developed utilizing various mechanisms of separation. The major metabolites proved to be isomeric glucuronides of the benzodioxane moiety hydroxylated at positions 6 or 7 and {2-(2-carboxyethyl)-3(2H)-pyridazinone}.

The interaction of MCI-154, a calcium sensitizer, and isoflurane on systemic and coronary hemodynamics in chronically instrumented dogs.

We conducted this study to determine the interaction of MCI-154, 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a calcium sensitizer, and isoflurane on myocardial contractility as well as systemic and coronary hemodynamics in chronically instrumented dogs after pharmacological autonomic nervous system activity blockade. MCI-154 increased heart rate and left ventricular function with no change in rate pressure product, pressure work index, and coronary blood flow, with a decrease in coronary vascular resistance (CVR) in the conscious state. Isoflurane decreased heart rate and left ventricular function, with a decrease in rate pressure product and pressure work index. Isoflurane also decreased CVR, but not coronary blood flow. The cardiovascular actions of MCI-154 during isoflurane anesthesia were qualitatively similar to those observed in the conscious state. In contrast to the finding in the conscious state, MCI-154 reversed the decrease in cardiac output and preload recruitable stroke work caused by isoflurane, but these are not significantly different from the effects of isoflurane alone. These results indicate that MCI-154 increases myocardial contractility and decreases CVR without changing calculated myocardial oxygen consumption during both the conscious state and isoflurane anesthesia. MCI-154, a calcium sensitizer, restores the myocardial contractility depressed by isoflurane and enhances the coronary vasodilating effect of isoflurane in chronically instrumented dogs.

Increased nitroglycerin-induced relaxation by genistein in rat aortic rings

The effect of genistein, a tyrosine kinase inhibitor, on nitroglycerin-induced relaxation was examined in rat aortic rings contracted by phenylephrine. In rat aortic rings, genistein (10 −5 M and 3×10 −5 M), a tyrosine kinase inhibitor, but not daidzein, an analogue of genistein, increased relaxation induced by nitroglycerin in a concentration-dependent manner. Iberiotoxin, an inhibitor of Ca 2+-activated K + channels, inhibited the relaxation induced by nitroglycerin, but it did not affect the effect of genistein. Glibenclamide, an inhibitor of ATP-sensitive K + channels, did not affect the relaxation induced by nitroglycerin. Theophylline, an inhibitor of cyclic AMP-dependent phosphodiesterase, increased the relaxation induced by nitroglycerin, and genistein (10 −5 M) failed to affect the relaxation induced by nitroglycerin in the presence of theophylline. Genistein also inhibited the activity of cyclic AMP-dependent phosphodiesterase. In addition, 6-[4-(4′-pyridyl)amino phenyl]-4,5-dihydro-3(2 H)-pyridazinone hydrochloride, an inhibitor of cyclic GMP-inhibitable cyclic AMP phosphodiesterase, inhibited the relaxation induced by nitroglycerin. These results suggest that, in the rat aortic rings, genistein inhibits cyclic AMP-dependent phosphodiesterase activities, resulting in the increase of the relaxation induced by nitroglycerin.

MCI-154, a Ca 2+ sensitizer, increases survival in cardiomyopathic hamsters

To assess the long-term efficacy of a Ca 2+ sensitizer MCI-154, 6-[4-(4′-pyridylamino)phenyl]-4,5-dihydro-3(2 H)-pyridazinone hydrochloride trihydrate, on chronic heart failure, we studied the effects of the agent on the life span of cardiomyopathic hamsters of the BIO-14.6 strain. At approximately 150 days of age, 210 male hamsters were randomly divided into three groups: MCI-154 0.1 mg kg −1 day −1 (MCI-154-low), MCI-154 1 mg kg −1 day −1 (MCI-154-high), and control group. The median survival time in control, MCI-154-low and MCI-154-high groups was 227, 243 and 260 days after the start of treatment, respectively. Final survival rate at 284 days in control, MCI-154-low and MCI-154-high groups was 0, 17.1 and 38.6%, respectively. The cumulative survival times in the two MCI-154 treated groups were significantly prolonged in comparison with that in the control group ( P<0.0001). Thus, the present study clearly showed that MCI-154 prolonged the life span of cardiomyopathic hamsters, suggesting that long-term therapy with MCI-154 would be promising in the treatment of congestive heart failure.

Effect of a cardiotonic agent, MCI-154, on the contractile properties of skinned skeletal muscle fibers

We have studied the effect of a cardiotonic agent, MCI-154 (6-[4-(4-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate), on the contractile properties and adenosine triphosphatase (ATPase) activity of chemically skinned rabbit skeletal muscle fibers. As in cardiac muscle, MCI-154 potentiated isometric tension and improved isometric tension cost at full Ca 2+ activation. It showed little Ca 2+-sensitizing effect. In contrast to its effect on cardiac muscle, however, MCI-154 decreased all the kinetic parameters tested (shortening velocity, the rate of rise of tension, and actomyosin ATPase activity). All the results are explainable if MCI-154 acts directly on skeletal actomyosin and inhibits a reaction step(s) of the ATPase cycle later than the force-generating event. The qualitative difference between cardiac and skeletal muscles in the responsiveness to this class of cardiotonic agents (MCI-154 and EMD 53998, a thiadiazinone derivative) is most readily understood if the agents have two independent actions, one on troponin and the other on actomyosin itself, the latter being dominant in skeletal muscle.

Effects of MCI-154, a new cardiotonic Ca 2+ sensitizer, on ventricular arrhythmias and membrane ionic currents

We examined whether a new positive inotropic agent with Ca 2+-sensitizing activity, MCI-154, 6-[4-(4-pyridylamino)phenyl]-4,5-dihydro-3-(2 H)-pyridazinone hydrochloride trihydrate, had deleterious effects on ventricular arrhythmias, since several phosphodiesterase III inhibitors have been shown to aggravate arrhythmias in our earlier studies. Continuous infusion of MCI-154 (1 μg/kg/min for 15 min) did not suppress or aggravate the arrhythmias generated in the two-stage coronary ligation-, digitalis- and adrenaline-induced canine arrhythmia models studied. Also in the case of a bolus injection of 30 μg/kg, MCI-154 did not aggravate the adrenaline-induced arrhythmias. To explain these results in vivo, a whole-cell voltage-clamp experiment on guinea-pig ventricular cells was performed. MCI-154 (10–100 μM) did not increase the inward Ca 2+ current under the condition where these currents were increased by isoprenaline. These results indicate that MCI-154 does not aggravate ventricular arrhythmias and does not act on membrane currents associated with arrhythmogenesis. Thus, MCI-154 may become a useful positive inotropic agent with little arrhythmogenic effect.

A novel class of cardiotonics. Synthesis and pharmacological properties of [4-(substituted-amino)phenyl]pyridazinones and related derivatives.

A series of [4-(substituted-amino)phenyl]pyridazinones and [4-(substituted-methyl)amino]phenyl]pyridazinones was synthesized and evaluated for inotropic activity in vitro and for cardiohemodynamic effects in vivo. Above all, 6-[4-(4-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (4, MCI-154) and 6-[4-(4-pyridylamino)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone hydrochloride (5) showed extremely potent positive inotropic activity along with vasodilating activity. Regarding dP/dtmax (an indicator for cardiac contractility), ED30's (doses that increased dP/dtmax by 30%) of compounds 4 and 5 were 8.5 +/- 1.9 and 4.4 +/- 0.6 micrograms/kg, respectively, where that of amrinone was 471.9 +/- 94.1 micrograms/kg. Structure-activity relationships of these series are presented, and a plausible model of receptor binding is discussed.

Determination of 4,4-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone hydrochloride, a new cardiotonic, in plasma and urine by reversed-phase high-performance liquid chromatography

Determination of 4,4-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone hydrochloride, a new cardiotonic, in plasma and urine by reversed-phase high-performance liquid chromatography

Pharmacological studies of a new analgesic agent, 2-phenyl-4-dimethylaminopropylamino-6-ethoxy-3(2H)pyridazinone hydrochloride (TM-3)

From an analgesic screening test of 2-phenyl-3 (2H) pyridazinone derivatives, synthesized by Takahashi et al., 2-phenyl-4-dimetylaminopropylamino-6-ethoxy-3 (2H) pyridazinone hydrochloride (TM-3) was discovered to have pronounced analgesic activity. In the present paper, the pharmacological effects, particularly analgesic and anti-inflammatory effects of TM-3, are compared with those of aminopyrine (AP) or phenylbutazone (PB). 1) In an analgesic test using modified Haffner's method on mice, the potency of TM-3 was approx. 6 times that of AP. 2) The analgesic effect of TM-3 tested by electric stimulation, hot plate and acetic acid stretching methods was equal to or more potent than that of AP. 3) TM-3 showed an inhibitory effect similar to that of PB on carrageenin, yeast and dextran-indued edema of rat paws. 4) In dermal tissue permeability tests of rats, TM-3 exhibited an equal or more potent inhibition as compared to PB. 5) In Winter's cotton pellet granuloma test, TM-3 tended to inhibit granulation. 6) TM-3 showed an antipyretic effect comparable to that of AP on T. T. G. -induced rabbit fiver. 7) TM-3 exhibited an uricosuric effect on uric acid or adenine-induced hyperuricemic rats. 8) TM-3 did not exhibit anti-convulsive, muscle-relaxant or hypnotic effects and influenced slightly spontaneous respiration, blood pressure, EEG and isolated auricular movement of rabbits. 9) The acute and subacute toxicities of TM-3 were lower than that of AP and the safety margin of TM-3 as an analgesic agent was considerably higher than that of AP.