Cardiovascular pharmacology of 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a novel and potent cardiotonic agent with vasodilator properties

The cardiovascular profile of 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (MCI-154), a novel cardiotonic agent structurally different from cardiac glycosides and beta-adrenoceptor agonists, was investigated in vivo. In anesthetized, open-chest dogs, MCI-154 (0.3-100 micrograms/kg i.v., bolus injection) produced dose-dependent increases in dP/dtmax and cardiac output, and decreases in arterial blood pressure and total peripheral resistance with a relatively small increase in heart rate. The positive inotropic effect of MCI-154 was more potent than those of amrinone and milrinone. In anesthetized, intact-chest dogs, infusion of MCI-154 (0.3-3 micrograms/kg/min i.v.) also exerted a positive inotropic effect. P.o. administrations of MCI-154 (10-300 micrograms/kg) increased dP/dtmax in conscious beagle dogs. The cardiotonic effect of MCI-154 was not attenuated by blockade of autonomic receptors, catecholamine depletion and prostaglandin synthesis inhibition. MCI-154 (0.3-30 micrograms i.a.) produced a direct vasodilator effect in the canine hind-limb. MCI-154 (3 and 30 micrograms/kg i.v.) was effective in heart failure models induced with high doses of propranolol or verapamil. The potent cardiotonic and vasodilator activities of MCI-154 revealed by the present study suggest that this agent would be an effective remedy for the treatment of heart failure.     

Cardiotonic agents. 6. Synthesis and inotropic activity of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones: ring-contracted analogues of imazodan (CI-914)

A series of 2,4-dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones was synthesized and evaluated for positive inotropic activity. Only compounds with two small alkyl groups at C-4 showed significant activity. The structure-activity relationships for optimal inotropic activity are presented and compared with those of the 4,5-dihydro-3(2H)-pyridazinone series. The phosphodiesterase inhibitory activity is also reported and correlated with the substitution pattern at C-4 in the pyrazolone ring.     

Cardiotonic agents. 4. Synthesis and biological evaluation of N-substituted 2,4,4a,5-tetrahydro-3H-indeno[1,2-c]pyridazin-3-ones: rigid structures derived from CI-930 and analogues

Several N-substituted 3H-indeno[1,2-c]pyridazinones (1-23) and a benzo[h]cinnolinone (24), which were designed as rigid structural modifications of 5-alkyl-4,5-dihydro-6-[4-N-substituted phenyl]-3(2H)-pyridazinones (ib-d), were synthesized and evaluated for positive inotropic activity. Most of these tricyclic pyridazinones (1-11, 14-15, 22-23) demonstrated potent positive inotropic activity comparable to the corresponding phenylpyridazinones related to I.     

MCI-154对心肌肥厚大鼠离体心脏的正性变力作用及其机制(英文)

目的　探讨钙增敏剂MCI 15 4〔6 [4 (4 吡啶氨基 )苯基 ] 4 ,5 二氢 3(2H)哒嗪酮〕对心肌肥厚心脏与对正常心脏的作用是否不同及有关的机制。方法　利用离体心脏灌流技术观察MCI 15 4对心肌肥厚大鼠心功能的影响 ;应用离子影像学分析系统同步测定心肌细胞钙浓度瞬变和细胞长度。结果　①MCI 15 410 0～ 4 0 0 μmol·L- 1范围内浓度依赖性地提高了心肌肥厚大鼠心功能的各项指标。在 4 0 0μmol·L- 1时 ,左室主动收缩压 (左室收缩峰压与左室舒张末压之差 )及左室压最大上升速率 (+dp/dtmax)与对照值相比显著增加 ,左室压最大下降速率(-dp/dtmax)有增高趋势 ,但无统计学意义 ;②MCI 15 410～ 10 0 μmol·L- 1在钙瞬变无明显改变情况下 ,呈浓度依赖性增加肥厚心肌细胞的缩短程度和钙敏感性 ;③MCI 15 4对肥厚心肌细胞钙瞬变的 5 0 %和90 %恢复时间影响不大。结论　在心肌肥厚大鼠心脏上 ,和在正常大鼠心脏上一样 ,MCI 15 4主要通过钙增敏作用发挥其正性变力作用。     

Imidazole-pyridine bioisosterism: comparison of the inotropic activities of pyridine- and imidazole-substituted 6-phenyldihydropyridazinone cardiotonics

We previously reported the structure-activity relationships (SAR), molecular structure, pharmacology, and molecular pharmacology of indolidan (LY195115), a potent and long-acting dihydropyridazinone cardiotonic. Our 6-phenyldihydropyridazinone SAR studies revealed the critical nature of the substituent at the para position of the phenyl ring. An acetamido substituent provided potent cardiotonic activity and we hypothesized that this may relate to the ability of the acetamide carbonyl to function as a hydrogen-bond acceptor. To further address this question, we prepared 15 (4,5-dihydro-6-[4-(3-pyridinyl)phenyl]-3(2H)-pyridazinone), the 3-pyridyl analogue of imazodan. As is the case with imazodan, this (pyridylphenyl)dihydropyridazinone possesses a nitrogen three atoms removed from the phenyl ring, but the molecular framework through which it is attached to the phenyldihydropyridazinone moiety is altered. After iv administration to pentobarbital-anesthetized dogs, inotropic ED50 values of 15, imazodan, and the parent compound, 4,5-dihydro-6-phenyl-3(2H)-pyridazinone, were 19.4, 50.1, and 6330 micrograms/kg, respectively. Thus, 15 is over 2-fold more potent than imazodan and 326-fold more potent than the parent, unsubstituted compound. These data, as well as data obtained with other congeners, are consistent with the hypothesis that a suitably oriented hydrogen-bond-acceptor site contributes to the high degree of inotropic potency observed with these dihydropyridazinone cardiotonics.     

Nonsteroidal cardiotonics. 2. The inotropic activity of linear, tricyclic 5-6-5 fused heterocycles

We previously reported the structure-activity relationships (SAR) of adibendan (1), a potent and long-acting cardiotonic. This paper describes the synthesis of a novel series of linear, tricyclic fused heterocycles of the 5-6-5 type. The compounds were evaluated for positive inotropic activity in anesthetized rats, cats, and dogs. Changes in left ventricular dP/dt were measured as an index of cardiac contractility. The increase in contractility was not mediated via stimulation of beta-adrenergic receptors. The data revealed the intrinsic positive inotropic activity of the parent compound of this series, 5,7-dihydro-7,7-dimethylpyrrolo[2,3-f]benzimidazol-6(1H)-one (2). The structural features that impart optimal inotropic activity are presented and compared with those of the 4,5-dihydro-3(2H)-pyridazinone series. The most potent compounds were evaluated orally in conscious dogs with implanted Konigsberg pressure transducers to measure ventricular pressures, and their effect on left ventricular dP/dt was compared with that of 1, pimobendan, and indolidan. After administration of 1 mg/kg, 1, 3, 7, 19, 22, 24, 31, 54, pimobendan, and indolidan were equipotent, but only with 1, 31, pimobendan, and indolidan, durations of action exceeded 6 h.     

7-Heteroaryl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin -2(1H)-one derivatives with cardiac stimulant activity

A series of 7-heteroaryl-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin++ +-2 (1H)-ones was synthesized and evaluated in dogs for cardiac stimulant activity. Compounds were obtained by a palladium-catalyzed cross-coupling reaction between a heteroarylzinc chloride and a 7-iodo-1,2,3,5-tetrahydroimidazo [2,1-b]quinazolin-2(1H)-one or by cyclization of an N-[(2-aminophenyl)methyl]glycinate with cyanogen bromide. Compared to the parent ring system (3), introduction of a 2,6-dimethylpyridin-3-yl (6), 2,4-dimethylimidazol-1-yl (7), or 1,2,4-triazol-1-yl (8) moiety at the 7-position led to a 13-17-fold increase in positive inotropic activity (percentage increase in dP/dtmax) in anesthetized dogs. Potency could be further enhanced with a 9-methyl substituent (10-12). The most potent member of the series, 7-(2,4-dimethylimidazol-1-yl)-9-methyl-1,2,3,5-tetrahydroimidaz o [2,1-b]quinazolin-2(1H)-one (11) (23% increase in dP/dtmax, 2 micrograms/kg), was 80 times more active than 3 and displayed a 5-fold advantage over milrinone. In conscious dogs, 6 elicited marked and sustained positive inotropic activity (decrease in QA interval) after oral administration (1 mg/kg), whereas 10-12 were 10 times more potent. 11 produced an obvious increase in cardiac contractility (20% increase in dP/dtmax) at low dose levels (25 micrograms/kg) while, after 100 micrograms/kg, the marked response (50% increase in dP/dtmax) was maintained for the whole 7-h test period. In these experiments, 11 had no effect on heart rate, and the compound also displayed exceptional selectivity for increasing the force rather than the rate of cardiac contraction (greater than 150% increase in dP/dtmax) in the Starling heart-lung preparation. These studies demonstrate that the tetrahydroimidazoquinazolinone nucleus is an effective bioisostere for the 2(1H)-quinolinone system and that 11 displays improved cardiac stimulant activity and duration of action when compared to milrinone.     

Some pyridazinone and phthalazinone derivatives and their vasodilator activities

In this study, 6-[(4-arylidene-2-phenyl-5-oxoimidazolin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone and 4-[(4-arylidene-2-phenyl-5-oxoimidazolin-1-yl)phenyl]-1(2H)-phthalazinone derivatives were synthesized by reacting 6-(4-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone or 4-(4-aminophenyl)-1(2H)-phthalazinone compound with different 4-arylidene-2-phenyl-5(4H)-oxazolone derivatives. The vasodilator activities of the compounds were examined both in vitro and in vivo. Some pyridazinone derivatives showed appreciable activity.     

Design and synthesis of a series of combined vasodilator/beta-adrenoceptor antagonists based on 6-arylpyridazinones

A series of new 6-[4-[[(aryloxy)acyl]amino]phenyl]-4,5-dihydropyridazinones have been synthesized and evaluated as combined vasodilator/beta-adrenoceptor antagonists and potential antihypertensive agents. Many of the early compounds displayed an unacceptably high level of intrinsic sympathomimetic activity (ISA) and a relatively short duration of action. Disubstitution in the 2,3-positions or in the 4-position of the aryloxy ring gave compounds with low ISA levels and, in some instances, improved duration of action. All of the compounds were vasodilators, but the 5-methylpyridazinone derivatives showed consistently greater antihypertensive activity than their 5-H lower homologues. Further detailed pharmacological investigations led to the selection of 6-[4-[3-[[2-hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]propionamido] phenyl]- 5-methyl-4,5-dihydro-3(2H)-pyridazinone (4t) (SK&F 95018) as a development candidate.     

Inhibition of cardiac phosphodiesterase III by the novel cardiotonic agent 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride

The novel cardiotonic agent 6[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (MCI-154) was investigated for its cardiovascular effects and its mechanism of action. In the anaesthetized rat MCI-154 (0.01-0.3 mumol/kg i.v., bolus injection) produced a dose-dependent increase in left ventricular dP/dt, and a decrease in mean arterial pressure. A relatively small increase in heart rate was observed. The drug inhibited selectively canine cardiac phosphodiesterase III (IC50 2.5 +/- 0.6 mumol/l). In skinned porcine trabeculae, MCI-154 produced only a small increase in the Ca2+-sensitivity of the contractile proteins. The results suggest that MCI-154 is a potent cardiotonic agent, and that inhibition of phosphodiesterase III may be a important component of this effect.     

Cardiotonic agents. 9. Synthesis and biological evaluation of a series of (E)-4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl)phenyl]ethenyl]-3 (2H)-pyridazinones: a novel class of compounds with positive inotropic, antithrombotic, and vasodilatory activities for the treatment of congestive heart failure

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.     

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 2nd communication: in vivo cardiovascular effects and bioavailability in dogs.

In vivo cardiovascular effects and bioavailability of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]-1,2,5,6- tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013), a novel cardiotonic agent, were investigated. In anesthetized dogs, intravenous administration of SCH00013 (0.3-10 mg/kg) increased maximum rate of rise in left ventricular pressure (LVdP/dtmax) in a dose-dependent manner with no change in heart rate (HR) and, at the dose of 3 mg/kg or higher, at which the increase in LVdP/dtmax reached the maximum, it decreased blood pressure. In conscious dogs, oral administration of SCH00013 (1-10 mg/kg) also increased LVdP/dtmax dose-dependently with no change in HR. The increase in the plasma concentration of orally administered SCH00013 (3 mg/kg) was parallel to the increase in LVdP/dtmax. The areas under the plasma concentration versus time curve (AUC0-24 h) after oral and intravenous administration of SCH00013 (3 mg/kg) were essentially identical (15.3 +/- 2.0 micrograms.h/ml and 16.5 +/- 2.1 micrograms.h/ml, respectively). These results suggest that oral bioavailability of SCH00013 is notably high. In conclusion, the positive inotropic effect of SCH00013 with neither elevation of HR nor excessive hypotension, as well as the high oral bioavailability of this compound, may provide a beneficial pharmacological treatment of the patients with congestive heart failure.     

2(1H)-quinolinones with cardiac stimulant activity. 3. Synthesis and biological properties of 6-imidazol-1-yl derivatives

A series of 6-imidazol-1-yl-8-methyl-2(1H)-quinolinones was synthesized and evaluated for cardiac stimulant activity in dogs. The majority of compounds were prepared from an appropriate 6-imidazol-1-yl-2(1H)-quinolinone precursor or by sulfuric acid catalyzed cyclization of an N-(4-heteroarylphenyl)-3-ethoxypropenamide. Introduction of a range of 5-substituents into 6-(2,4-dimethylimidazol-1-yl)-8-methyl-2(1H)-quinolinone (1) reduced inotropic activity in anesthetized dogs (percentage increase in dP/dtmax) although replacement of the 2-methyl group by iodo (10) or cyano (11) substituents was well tolerated. The 2-methyl-4-chloro (15) and 2-methyl-4-(methylthio) (22) derivatives displayed similar potency to 1 (40-50% increase in dP/dtmax, 10-12.5 micrograms/kg) and these compounds were 3-5 times more potent than milrinone. Introduction of iodo (14), cyano (16), or acetyl (17) substituents into the 4-position approximately halved inotropic activity. In conscious dogs, 11 (0.25 mg/kg) and 16 and 17 (0.125 mg/kg) produced similar increases in cardiac contractility (decrease in the QA interval) to 1 (0.125 mg/kg) and maximum responses were maintained for at least 3 h. Dose-related (25, 125, 250 micrograms/kg) cardiac stimulant activity was demonstrated by 17 and after the higher doses a marked response (approximately 30% increase in dP/dtmax) was still observed after 7 h, in contrast to milrinone. The substantial increases in cardiac contractility observed with 16 and 17 in the conscious dog were not accompanied by any tachycardia. These compounds also displayed an overwhelming selectivity for increasing the force of cardiac contraction (greater than 120% increase in dP/dtmax) rather than heart rate (5-10 beats/min decrease) in the Starling heart-lung preparation. As a result of this beneficial pharmacological profile, 6-(4-acetyl-2-methylimidazol-1-yl)-8-methyl-2(1H)-quinolinone (17, UK-66,838) was selected for preclinical development studies.     

Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate. 2nd communication: studies in dogs

The cardiovascular effects of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate (E-1020), a new nonglycoside, noncatechol cardiotonic agent, were investigated in dogs. In anesthetized dogs, E-1020 (10-100 micrograms/kg i.v.) dose-relatedly increased cardiac contractility (LV dP/dtmax), enhanced cardiac index and decreased systemic vascular resistance accompanying relatively small reduction in mean aortic pressure and a mild increase in heart rate. Coronary and femoral arterial blood flow were increased by either systemic intravenous or topical administration of E-1020. The degree of increase in myocardial oxygen consumption was only slight (10% at 30 micrograms/kg i.v.). The inotropic effect of E-1020 was not markedly affected by pretreatment with beta-adrenoceptor blockade, reserpine or other cardiotonic agents such as dobutamine or ouabain. In two experimental heart failure models induced by an excessive dose of propranolol or by coronary occlusion following volume-loading, E-1020 (30 micrograms/kg i.v.) rapidly reversed the cardiac depression. In chronically instrumented conscious dogs, E-1020 (30-100 micrograms/kg i.v. or 0.3-10 mg/kg p.o.) produced dose-dependent increases in LV dP/dtmax with minor increases in heart rate. E-1020 did not exacerbate arrhythmias of several experimental models in anesthetized dogs even at high dose of 100 micrograms/kg i.v. These results indicate that E-1020 is an intravenously and orally effective cardiotonic agent with vasodilating property, and that it may be beneficial in the treatment of acute and chronic congestive heart failure.     

Cardiotonic agents. 3. Synthesis and biological activity of novel 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones

Several 6-(substituted 1H-imidazol-4(5)-yl)-3(2H)-pyridazinones were synthesized and evaluated for positive inotropic activity. The 1H-imidazol-4-yl regioisomers 4,5-dihydro-6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (25a) and 6-(1-methyl-2-phenyl-1H-imidazol-4-yl)-3(2H)-pyridazinone (28a) were potent positive inotropic agents. By contrast, the corresponding 1H-imidazol-5-yl regioisomers 25b and 28b were only weak positive inotropic agents. Compounds 25a and 28a were also potent inhibitors of cardiac phosphodiesterase fraction III.     

Positive inotropic and vasodilatory actions of saterinone in vivo

The cardiovascular actions of the newly developed inotropic and alpha 1-receptor blocking agent saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy]phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) was investigated in small laboratory animals in vivo. Saterinone caused a direct inotropic effect in pithed guinea pigs without affecting heart rate. In the same animal species saterinone competitively antagonized the pressor effects of phenylephrine at inotropic doses. In conscious rabbits saterinone exerted dose-dependent increase in left ventricular dP/dtmax and in heart rate, whilst reducing arterial blood pressure in the same dose range. The drug dose-dependently antagonized phenylephrine as evidence of its alpha 1-receptor blocking effects in the conscious rabbit. The duration of alpha 1-receptor blockade was longer than the duration of inotropic effects. The onset of inotropic and vascular effects of saterinone was found to be simultaneous, when the drug was slowly infused into the femoral vein of anesthetized cats. The saterinone dose which caused a significant inhibition of the pressor effects of phenylephrine (comparable to prazosin) still caused a reduction of femoral perfusion pressure and systemic blood pressure in anesthetized cats pretreated with phenoxybenzamine. Thus in contrast to prazosin, which was rendered ineffective after phenoxybenzamine, saterinone possesses an additional mechanism for vasodilation. Saterinone exhibited good oral efficacy in spontaneously hypertensive rats and in conscious cats, in which an oral dose of 10-30 mg/kg significantly reduced arterial blood pressure or increased left ventricular dP/dtmax, respectively. Thus saterinone exerts in vivo direct positive inotropic and vasodilating effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dihydropyridazinone cardiotonics: synthesis and inotropic activity of 5'-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)spiro[cycloalkane- 1,3'-[3H]indol]-2'(1'H)-ones

In the 1,3-dihydro-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one series of cardiotonics, we found that a spirocycloalkyl ring may be annealed to the 3-position of the indolone moiety while retaining inotropic activity. An inverse relationship was found between spirocyloalkyl ring size and inotropic potency. ED50 values of the spirocyclopropane 10, spirocyclobutane 12, and spirocyclopentane 13 were 2.7, 35, and 133 micrograms/kg, respectively, following iv administration to pentobarbital-anesthetized dogs. The most potent compound prepared was 11 (5'-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)spiro[cyclopropane- 1,3'-[3H]indol]-2'(1'H)-one), the 4-methyl analogue of 10. This compound had an iv ED50 of 1.5 microgram/kg. Oral activity was evaluated by administering 50 micrograms/kg of 10 to conscious, chronically instrumented dogs. A 39% increase in LV dP/dt60 was observed, and an inotropic effect was demonstrable in excess of 7 h. Thus, the spirocyclic dihydropyridazinone inotropes are potent, long-acting, orally effective cardiotonics. Compound 11 was a potent inhibitor (IC50 = 13 nM) of cAMP phosphodiesterase derived from canine cardiac sarcoplasmic reticulum (SR-PDE). Importantly, -log IC50 values for inhibition of SR-PDE for this entire series of compounds were highly correlated (r = 0.949, p less than 0.02) with their inotropic -log ED50 values, supporting the hypothesis that inhibition of this enzyme contributes to the mechanism of action of the spirocyclic dihydropyridazinones.     

Synthesis and biological activity of the four stereoisomers of 6-[4-[3-[[2-hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]-propionamido] phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone, a combined vasodilator and beta-adrenoceptor antagonist

6-[4-[3-[[2-Hydroxy-3-[4-[2- (cyclopropylmethoxy)ethyl]phenoxy]propyl]amino]propionamido] phenyl]- 5-methyl-4,5-dihydro-3(2H)-pyridazinone (3) consists of a mixture of four stereoisomers, i.e., two racemates, as a consequence of the two asymmetric centers contained in the structure. An approximately equimolar mixture of these two racemates exhibits a novel combination of vasodilation and beta-adrenergic antagonist activity. This paper describes the synthesis of each of the four possible stereoisomers of 3 and provides clear evidence for the different pharmacological profile of each of the stereoisomers. The RA,SB isomer 3a has an overall profile slightly better than the complete mixture; the other three isomers all show reduced activity as vasodilators and/or beta-adrenergic antagonists.     

Structure-activity relationships of arylimidazopyridine cardiotonics: discovery and inotropic activity of 2-[2-methoxy-4-(methylsulfinyl)phenyl]-1H-imidazo[4,5-c]pyridine

Recently several noncatecholamine, nonglycoside cardiotonic drugs have been discovered that possess both inotropic and vasodilator activities in experimental animals and man. Prototypical compounds include amrinone, sulmazole, and fenoximone. We investigated the structural requirements necessary for optimal inotropic activity in a series of molecules containing a heterocyclic ring fused to 2-phenylimidazole and discovered that 2-phenylimidazo[4,5-c]pyridines were generally 5-10-fold more potent than analogous 2-phenylimidazo[4,5-b]pyridines (e.g., sulmazole) or 8-phenylpurines. Furthermore, all imidazo[4,5-c]pyridine analogues we tested were orally active; in contrast, only one of the imidazo[4,5-b]pyridine derivatives, sulmazole, was significantly active. One of several highly active compounds in the [4,5-c] series was 50 (LY175326, 2-[2-methoxy-4-(methylsulfinyl)phenyl]-1H-imidazo[4,5-c]pyridine hydrochloride). The structure-activity relationship of this series is presented and compared to that of the imidazo[4,5-b]pyridine and purine series.     

Cardiotonic agents. 2. Synthesis and structure-activity relationships of 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones: a new class of positive inotropic agents

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.