4-5-dihydro-6-(4-(imidazol-1-yl)phenyl)-5-methyl-3(2h)-pyridazinone and Heart-Failure

There are now several new CT drugs undergoing clinical study for the treatment of CHF. While most of these new agents are like digitalis in that they possess significant inotropic activity, they differ from digitalis in that they tend to also have pronounced vasodilator properties. Such compounds, because they are not pure CT agents, should not be regarded as true digitalis replacements. Despite the increased understanding about the cAMP cascade and about cardiac muscle contraction in general, the long search for a specific digitalis replacement cannot be regarded as having been accomplished. It should also be noted that the initial clinical assessment for any of these new compounds will be complicated by the fact that they are tested in only the latter stages of CHF where prognosis is very poor and the possibility of showing significant improvement in mortality is extremely difficult. It will be unfortunate if the potential for positive inotropic agents (pure CT drugs) is compromised by clinical studies that employ mixed inotropic-vasodilator compounds in extremely sick patient populations. The continued use of the digitalis glycosides for such a long period of history implies that at least some subpopulation of CHF patients should derive benefit from therapy with an appropriately selective CT drug. Neither the appropriate drug nor the appropriate specific patient population, both of which are needed to properly address the eventual role of inotropic therapy in CHF, have, as yet, been identified.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Cardiotonic Agents; Cyclic AMP; Digitalis Glycosides; Heart Failure; Humans; Myocardial Contraction; Receptors, Adrenergic, beta; Structure-Activity Relationship

While the acute hemodynamic efficacy and safety of the novel inotropic agents are well recognized, their long-term effects on symptoms, quality of life, and survival, in patients with chronic congestive heart failure, are controversial. Such controversy may result from a poor understanding of the disease process and its progression, unrealistic expectations on the potential benefits of enhancing myocardial contractility at an advanced stage of the disease, and the lack of knowledge of the precise mechanisms of action of the novel inotropic agents. To put into perspective the role of the novel inotropic agents in the treatment of chronic congestive heart failure, the effects of dobutamine (a synthetic catecholamine which is the most potent inotropic agent currently available) were reviewed. Changes in cardiac performance, myocardial contractility and metabolism, and exercise capacity were studied in patients with chronic congestive heart failure of variable severity. The acute hemodynamic effects and the mechanism of action of the novel inotropic agents were then reviewed and compared to those of dobutamine. Which patients with chronic congestive heart failure who are the most likely to benefit from therapy with the novel inotropic agents, and the therapeutic limitations of these agents are discussed. Lastly, the difficulties of selecting the right endpoints to demonstrate the long-term efficacy of the novel inotropic agents are considered.

Topics: Amrinone; Animals; Cardiotonic Agents; Dobutamine; Enoximone; Heart Failure; Hemodynamics; Humans; Imidazoles; Milrinone; Myocardial Contraction; Physical Exertion; Pyridazines; Pyridones; Time Factors

A novel series of analogues of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl) phenyl]ethenyl]-3(2H)-pyridazinone was synthesized as a variation on the imazodan series. The compounds were evaluated for (i) hemodynamic activity, (ii) cyclic AMP-phosphodiesterase inhibitory activity (human platelets and guinea pig heart tissue), and (iii) platelet aggregation inhibitory activity. The insertion of the ethenyl moiety between the phenyl and dihydropyridazinone rings produced novel compounds that retained the potent inotropic/vasodilator activity of the parent imazodan series and enhanced the platelet aggregation inhibitory potency. Compound 3d, the most potent in this series, demonstrated in vivo antithrombotic activity. The synthesis and the biological activity of these new pyridazinone analogues are reported.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cardiotonic Agents; Dogs; Female; Fibrinolytic Agents; Heart Failure; Humans; Imidazoles; Male; Myocardial Contraction; Platelet Aggregation; Pyridazines; Structure-Activity Relationship; Vasodilator Agents

Hybridization of structural elements of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline ring system common to the cyclic AMP (cAMP) phosphodiesterase (PDE) inhibitors lixazinone (RS-82856, 1) and anagrelide (3) with complementary features of other PDE inhibitor cardiotonic agents prompted the design and synthesis of the title compounds 7a-d, 11, 12, and 13a,b. The necessary features of these compounds were determined within the framework of the proposed active-site models for the high affinity form of cAMP PDE inhibited by cGMP (type IV). Evaluation of these targets, both in vitro as inhibitors of platelet or cardiac type IV PDE or in vivo as inotropic agents in the pentobarbital-anesthetized dog model of congestive heart failure, showed that these structure possessed negligibly enhanced activities over the parent heterocyclic system, and remained significantly inferior to 1 in all respects. This difference is ascribed to the absence of the N-cyclohexyl-N-methylbutyramidyl-4-oxy side chain of 1. The proposal that the acidic lactam-type functionality, common to the type IV PDE inhibitor inotropic agents such as 4-6 and 8-10, mimics the polarizable cyclic phosphate moiety of cAMP suggested that the side chain of 1 may function as an effective surrogate for selected characteristics of the adenine portion of cAMP. However, the results of this study show that incorporation of adenine-like hydrogen-bonding functionalities common to other type IV PDE inhibitors into the 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline system did not enhance activity to the levels observed for 1 and analogues. These observations, coupled with the kinetic pattern of inhibition of type IV PDE observed for 1 and analogues, suggest that access to a secondary, lipophilic-tolerant binding site, possibly coincident with the adenine binding domain, and adjacent to the catalytic ribose-phosphate binding site of platelet and cardiac type IV PDE, is responsible for the increased potency of these compounds.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Blood Platelets; Cardiotonic Agents; Dogs; Drug Evaluation; Heart Failure; Humans; Myocardium; Platelet Aggregation; Quinazolines; Structure-Activity Relationship

The hemodynamic and clinical effects of parenteral and oral CI-930, a new phosphodiesterase type III inhibitor with combined vasodilator and inotropic properties, were studied in 12 patients with severe congestive heart failure refractory to therapy including captopril. The maximum response to dobutamine was also determined. Intravenous CI-930 increased cardiac index from 1.73 +/- 0.48 to 2.38 +/- 0.55 L/min/m2, and reduced pulmonary capillary wedge pressure from 19.2 +/- 7.9 to 12.5 +/- 6.4 mm Hg, mean right atrial pressure from 7.5 +/- 6.3 to 3.6 +/- 4.0 mm Hg, and systemic vascular resistance from 2288 +/- 860 to 1711 +/- 611 dynes . sec . cm-5 (p less than 0.001 for all). Heart rate and mean systemic arterial pressure were unchanged. The increment in cardiac index produced by dobutamine was higher than for CI-930, 2.68 +/- 0.55 vs 2.38 +/- 0.55 L/min/m2, p less than 0.001. However, reduction in pulmonary capillary wedge pressure tended to be less with dobutamine, 15.7 +/- 7.9 vs 12.5 +/- 6.4 mm Hg (NS). Hemodynamic benefits of oral CI-930 were equivalent to that of the parenteral drug. Duration of action was 9 to 12 hours. Chronic therapy resulted in subjective improvement in approximately 50% of patients. Exercise capacity, assessed by maximum oxygen consumption, was unchanged, 8.4 +/- 3.3 vs 9.8 +/- 3.4 ml/kg/min (NS). No overt laboratory manifestations of toxicity were observed.

Topics: Cardiotonic Agents; Dobutamine; Dose-Response Relationship, Drug; Female; Heart Failure; Hemodynamics; Humans; Middle Aged; Phosphodiesterase Inhibitors; Pyridazines; Time Factors

CI-930, a new type III phosphodiesterase inhibitor, was evaluated for treatment of refractory congestive heart failure. The hemodynamic, pharmacokinetic and clinical response to the drug was determined in 10 patients. At the peak plasma concentration after intravenous CI-930, cardiac index increased from 2.0 to 2.7 liters/min/m2 (p less than 0.002), pulmonary artery wedge pressure decreased from 26 to 17 mm Hg (p less than 0.001) and systemic vascular resistance decreased from 1,999 to 1,471 dynes cm-5 (p less than 0.05). Heart rate and blood pressure did not change significantly. Similar changes were observed with oral CI-930. Peak CI-930 plasma concentration occurred 1.2 +/- 0.8 hours after oral administration. Beneficial hemodynamic effects were sustained 12 to 18 hours after the oral dose. The sustained hemodynamic effects observed after oral administration appear to be related to an active metabolite of CI-930 that has prolonged duration of action and slow washout. The drug was well tolerated and has potential for treatment of congestive heart failure.

Topics: Administration, Oral; Aged; Animals; Cardiomyopathy, Dilated; Cricetinae; Female; Heart Failure; Hemodynamics; Humans; Kinetics; Male; Middle Aged; Phosphodiesterase Inhibitors; Pyridazines; Time Factors

The phosphodiesterase inhibitor CI-930 hydrochloride exerts a positive inotropic and vasodilator effect in experimental animals. The acute hemodynamic and hormonal effects of intravenous CI-930 were studied in 9 patients with severe congestive heart failure. At 60 minutes of drug infusion, there was an increase in cardiac index (2.7 +/- 0.9 vs 2.0 +/- 0.7 liters/min/m2, p less than 0.01) and positive dP/dt (1,390 +/- 470 vs 1,100 +/- 300 mm Hg/s, p less than 0.02). Additionally, there were decreases in mean systemic arterial (78 +/- 16 vs 86 +/- 15 mm Hg, p less than 0.01), mean right atrial (5 +/- 3 vs 9 +/- 4 mm Hg, p less than 0.02), mean pulmonary arterial (27 +/- 11 vs 37 +/- 9 mm Hg, p less than 0.01) and LV end-diastolic (19 +/- 8 vs 28 +/- 6 mm Hg, p less than 0.01) pressures. Heart rate did not change (97 +/- 17 vs 97 +/- 22 beats/min). The inotropic response correlated significantly (r = 0.70, p less than 0.05) with the dose of CI-930. Plasma renin activity did not change significantly (from 16 +/- 9 to 23 +/- 15 ng/ml/hour), nor did plasma norepinephrine or arginine vasopressin levels. The plasma atrial natriuretic peptide level decreased (from 153 +/- 97 to 83 +/- 35 pg/ml, p less than 0.02). These findings suggest that intravenous CI-930 hydrochloride is a useful therapeutic agent in congestive heart failure and that its use does not appear to further activate potentially deleterious hormonal systems.

Topics: Heart Failure; Hemodynamics; Hormones; Humans; Male; Phosphodiesterase Inhibitors; Pyridazines; Severity of Illness Index; Time Factors

A series of 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and related compounds were synthesized and evaluated for positive inotropic activity. Most members of this series produced dose-related increases in myocardial contractility that were associated with relatively minor increases in heart rate and decreases in systemic arterial blood pressure. Introduction of a methyl substituent at the 5-position of 1 (CI-914) produced the most potent compound in this series (11, CI-930). Compound 1 is more potent than amrinone whereas compound 11 is more potent than milrinone. The inotropic effects of 1 and 11 are not mediated via stimulation of beta-adrenergic receptors. Selective inhibition of cardiac phosphodiesterase fraction III represents the principal component of the positive inotropic action of 1 and 11.

Topics: Adrenergic beta-Antagonists; Animals; Cardiotonic Agents; Chemical Phenomena; Chemistry, Physical; Dogs; Heart Failure; Imidazoles; Myocardial Contraction; Pyridazines; Structure-Activity Relationship

Topics: Animals; Cardiotonic Agents; Dogs; Guinea Pigs; Heart Failure; Myocardial Contraction; Phosphodiesterase Inhibitors; Pyridazines