Hemodynamic and electrophysiological effects of a novel positive inotropic drug, OPC-8212, in normal and "failing" guinea pig heart preparations

OPC-8212, 3,4-dihydro-6-[4-(3,4-dimethoxy-benzoyl)-1-piperazinyl]-2 (1H)-quinolinone, significantly decreased heart rate and increased contractility (+ dP/dt) and coronary flow in isolated, perfused guinea pig Langendorff and work-performing heart preparations. The effect on contractility, but not on coronary flow, was significantly greater when the negative chronotropic effect was prevented by pacing. In guinea pig hearts made incompetent by aortic stenosis, OPC-8212 produced a significant increase in contractility and coronary flow and greater negative chronotropic effects than in control hearts. OPC-8212 improved the work performance of normal and "failing" isolated work-performing guinea pig hearts during pressure load and during volume load. In electrophysiological studies, OPC-8212 enhance Vmax, amplitude, and duration of fast action potentials (APs) in guinea pig papillary muscles. Tetraethylammonium (TEA)-induced slow APs were also potentiated with respect to Vmax, amplitude, and duration. OPC-8212 in the absence of TEA also lowered the voltage threshold for inducing the slow APs. Positive inotropic effects, but not the slow APs, of guinea pig papillary muscles were greatly enhanced by OPC-8212 at higher frequencies of stimulation (2-3 Hz), indicating an important mechanism of action that may be at least in part independent of Isi.     

Cardiovascular studies of 5-(3-tert-butylamino-2-hydroxy) propoxy-3,4-dihydrocarbostyril hydrochloride (OPC-1085), a new potent beta-adrenergic blocking agent

The beta-adrenergic blocking and hemodynamic properties of 5-(3-tert-butyl-amino-2-hydroxy) propoxy-3,4-dihydrocarbostyril hydrochloride (OPC-1085) were investigated and compared with those of propranolol and pindolol on myocardial contractile force, heart rate and arterial blood pressure in pentobarbital anesthetized dogs. OPC-1085 showed almost the same beta-adrenergic blocking potency as pindolol, but was approximately 30 and 20 times stronger than propranolol against isoproterenol and cardiac nerve stimulation, respectively. Slight negative inotropic and chronotropic responses were observed with OPC-1085 in effective blocking doses from 1 to 10 mug/kg but were converted to positive ones in doses from 30 to 3000 mug/kg in non-reserpinized dogs. In reserpinized dogs, both OPC-1085 and pindolol induced only positive responses. These responses were more evident with OPC-1085.     

Clinical overview of the novel inotropic agent toborinone

Toborinone (OPC-18790, Otsuka Pharmaceutical Co. Ltd, 2(1H) -quinolone,6-[3-[ [3,4-dimethoxyphenyl)methyl] amino]-2-hydroxy prop oxyl]-,(.+-.)-) is a novel iv. inotropic agent. Positive inotropic effects are produced by PDE inhibition with the resulting increase in cAMP and intracellular calcium levels. Unlike other inotropic agents that increase cAMP, there is an absence of positive chronotropic effects, which are attributed to prolongation of the action potential due to blockade of delayed rectifier currents. There is also marked venous and arterial vasodilating properties. The absence of heart rate increases results in decreased myocardial oxygen consumption compared with conventional inotropes. Studies in human heart failure patients have been consistent with previous work in animal studies, confirming the effects of toborinone as being positive inotropy (relatively weak), marked arterial and venous vasodilatation and absence of increase in myocardial oxygen consumption. Data regarding safety in larger clinical trials, particularly regarding arrhythmias, is at present unavailable. This information will determine whether this agent becomes an accepted iv. therapeutic option for congestive heart failure.     

2(1H)-quinolinones with cardiac stimulant activity. 2. Synthesis and biological activities of 6-(N-linked, five-membered heteroaryl) derivatives

A series of 6-(N-linked, five-membered heteroaryl)-2(1H)-quinolinone derivatives was synthesized and evaluated for cardiotonic activity. Most compounds were prepared by sulfuric acid catalyzed cyclization of an N-(4-heteroarylphenyl)-3-ethoxypropenamide or by condensation of a 2-amino-5-heteroarylbenzaldehyde or -acetophenone derivative with the ylide derived from triethyl phosphonoacetate. In anesthetized dogs, 6-imidazol-1-yl-8-methyl-2(1H)-quinolinone (3; 25 micrograms/kg) produced a greater increase in cardiac contractility (percentage increase in dP/dt max) than alternative 6-(five-membered heteroaryl)-substituted analogues (4-8). Introduction of 4-methyl (10) or 2,4-dimethyl (13) substituents into the imidazole ring of 3 produced a marked increase in inotropic activity, and these compounds were some 10 and 5 times more potent than milrinone. Most of these quinolinones also displayed positive inotropic effects (decrease in QA interval) in conscious dogs after oral administration (0.0625-1 mg/kg) and in many cases (3, 5-7, 9, 11, 13, 16) there was little difference in activities at both the 1- and 3-h time points. Compound 13 (62.5, 125, 250 micrograms/kg po) demonstrated dose-related cardiac stimulant activity which, in contrast to milrinone, was maintained over the whole 7-h test period. No changes in heart rate were detected at any dose level and compounds 3, 9, 10, and 13 also displayed high selectivity for the stimulation of cardiac contractile force rather than heart rate in the Starling dog heart-lung preparation. Increases in dP/dt max of approximately 50% were accompanied by heart rate changes of less than 10 beats/minute. Physicochemical measurements gave a log P of 1.64 for 13 with pKa values of 7.13 +/- 0.04 and 11.5 +/- 0.2 for the imidazole and quinolinone moieties, respectively. X-ray structural analysis of 13 showed the imidazole and quinolinone rings at 52 degrees to one another in close agreement with the minimum-energy conformation (30 degrees) suggested by PCILO calculations. 6-(2,4-Dimethylimidazol-1-yl)-8-methyl-2-(1H)-quinolinone (13, UK-61,260) is currently undergoing phase II clinical evaluation in congestive heart failure patients.     

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.     

Comparison of the Arrhythmogenic Actions of (-)-Isoprenaline, Dobutamine and the selective beta 1-adrenoceptor agonist, (+/-)-(1-[3',4'-dihydroxyphenoxy] -2-hydroxy-[3",4"-dimethoxy phenethylamino]-propane)-oxalate (Ro 363)

In guinea-pig left atrial preparations, concentrations of (-)-isoprenaline and (+/-)-(1-[3',4'-dihydroxyphenoxy] -2-hydroxy-[3",4"-dimethoxyphenethylamino]-propane)-oxalate (Ro 363) causing maximal inotropic responses produced small reductions in effective refractory period. Dobutamine had little effect on the refractory period except at supramaximal inotropic concentrations, when increases in effective refractory period were produced. Isolated perfused heart preparations from guinea-pigs developed arrhythmic contractions following the administration of (-)-isoprenaline, Ro 363 and dobutamine in doses producing 70-100% of their maximal chronotropic responses. The arrhythmogenic activity of the three agonists paralleled their respective beta 1-receptor stimulant properties. In chloralose-anaesthetized cats, the 3 agonists, (-)-isoprenaline, Ro 363 and dobutamine, when compared to epinephrine (adrenaline), were essentially devoid of arrhythmogenic activity in animals in which cardiac sensitization was induced by 3-dimethylamino-2-methyl-2-phenoxypropiophenone hydrochloride (U-0882) or halothane. However, all 3 agonists elicited ventricular arrhythmias following the administration of subarrhythmic doses of ouabain and increased the number of subauricular escape beats which occurred during vagal nerve stimulation in non-ouabain treated animals. In all cases the arrhythmogenic activity of the drugs paralleled their relative activity for eliciting rises in heart rate.     

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.     

Clinical overview of the novel inotropic agent toborinone

Toborinone (OPC-18790, Otsuka Pharmaceutical Co. Ltd, 2(1H) -quinolone,6-[3-[ [3,4-dimethoxyphenyl)methyl] amino]-2-hydroxy prop oxyl]-,(.+-.)-) is a novel iv. inotropic agent. Positive inotropic effects are produced by PDE inhibition with the resulting increase in cAMP and intracellular calcium levels. Unlike other inotropic agents that increase cAMP, there is an absence of positive chronotropic effects, which are attributed to prolongation of the action potential due to blockade of delayed rectifier currents. There is also marked venous and arterial vasodilating properties. The absence of heart rate increases results in decreased myocardial oxygen consumption compared with conventional inotropes. Studies in human heart failure patients have been consistent with previous work in animal studies, confirming the effects of toborinone as being positive inotropy (relatively weak), marked arterial and venous vasodilatation and absence of increase in myocardial oxygen consumption. Data regarding safety in larger clinical trials, particularly regarding arrhythmias, is at present unavailable. This information will determine whether this agent becomes an accepted iv. therapeutic option for congestive heart failure.     

Synthesis of 2-(4-substitutedbenzyl-[1,4]diazepan-1-yl)-n-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides as inotropic agents

In an attempt to search for more potent positive inotropic agents, a series of N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(substitutedbenzyl-[1,4]diazepan-1-yl)acetamides were synthesized and evaluated for positive inotropic activity by measuring left atrium stroke volume in isolated rabbit heart preparations. Some of these derivatives exhibited favorable activity compared with the standard drug, milrinone, among which 2-(4-(4-methylbenzyl)-[1,4]-diazepan-1-yl)-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide (6m) was the most potent, increasing stroke volume by 8.38±0.16% (milrinone 2.45± 0.06%) at 3 x 10(-5) m. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

Potent effects of novel anti-platelet aggregatory cilostamide analogues on recombinant cyclic nucleotide phosphodiesterase isozyme activity

The inhibitory potential of novel anti-platelet aggregatory cilostamide analogues on phosphodiesterase (PDE) isozyme activities was investigated with recombinant PDE isozymes expressed in a baculovirus/ Sf9 expression system. The recombinant enzymes (PDE1-PDE5 and PDE7) showed Km values and sensitivities to selective inhibitors similar to those reported previously for native enzymes purified from tissues. The cyclooctylurea derivative OPC-33540 (6-[3-[3-cyclooctyl-3-[(1R*,2R*)-2-hydroxycyclohexyl]ureido]-propoxy]-2(1H)-quinolinone) inhibited recombinant PDE3A (IC50 = 0.32 nM) more potently and selectively than the classical PDE3 inhibitors cilostamide, cilostazol, milrinone, and amrinone. The cyclopropylurea derivative OPC-33509 [(-)-6-[3-[3-cyclopropyl-3-[(1R,2R)-2-hydroxycyclohexyl]ureido]-propoxy]-2(1H)-quinolinone] was less potent (IC50 = 0.10 microM) than OPC-33540, demonstrating that the cyclooctyl moiety was important for a potent inhibitory effect. In platelets, OPC-33540 potentiated cyclic AMP accumulation concentration-dependently in both the absence and the presence of 3 nM prostaglandin E1 (PGE1) (doubling concentrations: 32.5 and 6.2 nM, respectively). OPC-33540 inhibited thrombin-induced platelet aggregation potently (Ic50 = 27.8 nM). The anti-platelet aggregation effect also was stimulated in the presence of 3 nM PGE1 (IC50 = 6.0 nM). There was a good correlation between the IC50 values of PDE3 inhibitors in this study for recombinant PDE3A activity and their IC50 values for thrombin-induced platelet aggregation (r = 0.998). These data demonstrated that OPC-33540 is a highly selective and potent PDE3 inhibitor and a useful probe for identification of the intracellular functions of PDE3.     

Characterization of human cytochrome p450 enzymes involved in the metabolism of cilostazol.

Cilostazol (OPC-13013; 6-[4-(1-cyclohexl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone) is widely used as an antiplatelet vasodilator agent. In vitro, the hydroxylation of the quinone moiety of cilostazol to OPC-13326 [6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-4-hydroxy-2(1H)-quinolinone], is the predominant route, and the hydroxylation of the hexane moiety to OPC-13217 is the second most predominant route. This study was carried out to identify and kinetically characterize the human cytochrome P450 (P450) isozymes responsible for the formation of the two major metabolites of cilostazol, namely, OPC-13326 and OPC-13217 [3,4-dihydro-6-[4-[1-(cis-4-hydroxycyclohexyl)-1H-tetrazol-5-yl)butoxy]-2(1H)-quinolinone)]. In in vitro studies using 14 recombinant human P450 isozymes, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP3A4, CYP3A5, and CYP4A11, cilostazol was metabolized to OPC-13326 mainly by CYP3A4 (K(m) = 5.26 muM, intrinsic clearance (CL(int)) = 0.34 microl/pmol P450/min), CYP1B1 (K(m) = 11.2 microM, CL(int) = 0.03 microl/pmol P450/min), and CYP3A5 (K(m) = 2.89 microM, CL(int) = 0.05 microl/pmol P450/min) and to OPC-13217 mainly by CYP3A5 (K(m) = 1.60 microM, CL(int) = 0.57 microl/pmol P450/min), CYP2C19 (K(m) = 5.95 microM, CL(int) = 0.16 microl/pmol P450/min), CYP3A4 (K(m) = 5.35 microM, CL(int) = 0.10 microl/pmol P450/min), and CYP2C8 (K(m) = 33.8 microM, CL(int) = 0.009 microl/pmol P450/min). The present study showed that the two major metabolites of cilostazol in vitro, namely, OPC-13326 and OPC-13217, are mainly catalyzed by CYP3A4 and CYP3A5, respectively.     

Haemodynamic effects of Ro 13-6438, a new inotropic agent with vasodilating properties

The chemical class 1,5 dihydroimidazo (2,1-6) guinazolin-2(3H)ones has been shown to have positive inotropic activity, some of its members displaying a favourable ratio between positive inotropic and chronotropic activity. This study was designed to determine the cardiovascular properties of Ro 13-6483, a non-glycoside, non-catechol positive inotropic agent, in anaesthetized, open chest mongrel dogs. Ro 13-6483 (1 mg/kg) was administered intravenously over a 5-min period to 6 dogs. Haemodynamic changes were measured continuously over a period of 45 min. Ro 13-6438 increased stroke volume by 61.9% (p less than 0.001) and cardiac output by 53.3% (p less than 0.001). Systolic and diastolic blood pressure decreased significantly (p less than 0.01). Heart rate did not change. The lowering of the blood pressure, without a significant increase in heart rate, observed after Ro 13-6483 administration might prove to be of value in patients with congestive heart failure, since Ro 13-6483 would reduce afterload and improve the competency of the heart, in addition to the positive inotropic effects.     

Cardiovascular actions of DPI 201-106, a novel cardiotonic agent

DPI 201-106 (4-[3-(4-diphenylmethyl-1-piperazinyl)-2-hydroxypropoxy]-1H-indole -2- carbonitrile) is characterized by a marked cardiotonic activity. The compound exerted positive inotropic effects in anesthetized and conscious dogs, pithed open-chest cats, and isolated hearts of cardiomyopathic hamsters and vanadate-treated guinea-pig atria. Left ventricular dP/dtmax was increased in anesthetized dogs after i.v. injection of 0.2 and 2 mg/kg DPI 201-106 (34 +/- 6 and 104 +/- 18%, respectively) and in unanesthetized dogs after oral doses of 2-8 mg/kg (22 +/- 3 to 50 +/- 5%, respectively). In most experiments, the compound lowered blood pressure and heart rate. Stroke work and left ventricular work were almost unaffected by DPI 201-106, and oxygen consumption and cardiac efficiency remained unchanged in open-chest dogs. Studies of the mechanism of action of DPI 201-106 lead to the conclusion that its positive inotropic effect is not explainable either by beta-stimulation or by liberation of catecholamines. This was shown in anesthetized dogs and pithed open-chest cats pretreated with propranolol and reserpine.     

New positive inotropic agent OPC-8212 modulates single Ca2+ channels in ventricular myocytes of guinea pig

The effects of a new positive inotropic drug, OPC-8212 (a quinolinone derivative, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1 -piperazinyl]-2(1H)-quinolinone), on whole-cell and single-channel calcium currents of guinea pig ventricular myocytes were studied by the patch-clamp method. OPC-8212 increased whole-cell calcium currents in a concentration-dependent manner. The concentration-response curve was fitted by a single binding site model that has an ED50 of 2.7 microM. At the single-channel level, OPC-8212 increased calcium currents mainly by increasing the probability of channel opening on depolarization; the open times were slightly increased, but single-channel conductance did not change. The actions of OPC-8212 on single calcium channel currents were compared with those of forskolin, isoproterenol, and caffeine, agents that cause positive inotropic effects associated with an increase in cytoplasmic cyclic AMP level, and with those of the dihydropyridine calcium channel agonist (-)Bay K 8644, an agent that has a positive inotropic effect but does not act through cyclic AMP. OPC-8212 increased calcium currents in a manner that resembled the actions of forskolin, isoproterenol, and caffeine rather than the actions of (-)Bay K 8644. We suggest that activation of calcium currents by OPC-8212 is mediated by an elevation of intracellular cyclic AMP. Since OPC-8212 produces bradycardia and antitachycardiac effects in animals and humans, unlike agents that increase cyclic AMP, additional effects on other currents are likely.     

6-(4-酰基-1-哌嗪乙酰氨基)-3,4-二氢-2(1H)-喹啉酮类化合物的合成及正肌力活性初探

目的 :寻找具有正性肌力活性的化合物。方法 :根据文献报道的二氢喹啉酮类正性肌力药物的结构特点 ,设计、合成了其类似物。以苯胺为起始原料经多步合成 ,对所得化合物用离体豚鼠心脏与主动脉观察了心肌收缩力、扩血管作用及心率。结果 :合成了 1 0个 6 ( 4 酰基 1 哌嗪乙酰氨基 ) 3 ,4 二氢 2 ( 1H) 喹啉酮类化合物 ( 4a～ 4j) ,均为未见文献报道的化合物。结论 :初步药理试验表明 ,化合物 ( 4h)显示了正性肌力及扩血管活性。     

Aortic vascular and atrial responses to (+/-)-1-O-octadecyl-2-acetyl-glyceryl-3-phosphorylcholine.

The effects of (+/-)-1-O-octadecyl-2-acetyl-glyceryl-3-phosphorylcholine (octadecyl-AGPC) were studied in three types of aortic vascular smooth muscle preparations, namely, strips, rubbed and unrubbed rings, and an atrial preparation in normotensive rats. In the resting tension state, octadecyl-AGPC did not elicit significant contractions in either rubbed or unrubbed ring preparations at concentrations lower than 1 X 10(-4) M. However, at a concentration of 3 X 10(-4) M, octadecyl-AGPC markedly contracted both types of ring preparations. This contractile response was partially antagonized by pretreatment with reserpine and completely blocked by phentolamine (1 X 10(-6) M). In preparations contracted with noradrenaline (NA), octadecyl-AGPC elicited biphasic responses in intact ring preparations; an initial relaxation followed by contraction. Octadecyl-AGPC induced only a slight contraction in strips and a slight relaxation in the rubbed ring preparation. Octadecyl-AGPC did not elicit any significant effect on chronotropy or inotropy at concentrations up to 3 X 10(-5) M. When the concentration was 1 X 10(-4) M, octadecyl-AGPC produced significant positive chronotropic and inotropic effects on spontaneously beating right and electrically driven left atrial preparations, respectively. Both effects were blocked by propranolol (5 X 10(-8) M); reserpine pretreatment antagonized only the chronotropic response. In [3H]-dihydroalprenolol [( 3H]-DHA) binding studies, octadecyl-AGPC had a Kd of 427.85 microM and thus was much less potent than isoprenaline (Kd = 465.10 nM) or propranolol (Kd = 4.4 nM) in displacing [3H]-DHA in rat cardiac membrane preparations.(ABSTRACT TRUNCATED AT 250 WORDS)     

NMDA antagonist activity of (+/-)-(2SR,4RS)-4-(1H-tetrazol-5-ylmethyl)piperidine-2-carboxylic acid resides with the (-)-2R,4S-isomer.

The tetrazole-substituted amino acid (+/-)-(2SR,4RS)-4-(1H-tetrazol-5-ylmethyl)pip eri dine-2-carboxylic acid (LY233053, (+/-)-1) was resolved into its constituent enantiomers by treatment of a key intermediate in the synthesis of the racemic amino acid, ethyl (+/-)-cis-4-(cyanomethyl)-N-allylpiperidine-2-carboxylate, with either 2S,3S- or 2R,3R-di-p-toluoyltartaric acid. These resolved amines were then converted as for the racemate to the amino acids (-)-1 and (+)-1. The activity of this potent and selective NMDA antagonist was found to reside with the (-)-isomer of 1 (LY235723). X-ray crystallographic analysis of the 2S,3S-di-p-toluoyltartaric acid salt of ethyl cis-4-(cyanomethyl)-N-allylpiperidine-2-carboxylate showed that the resolved amine, and thus (-)-1, possessed the 2R,4S absolute stereochemistry. Affinity for the NMDA receptor was determined using the specific radioligand [3H]-(2SR,4RS)-4-(phosphonomethyl)piperidine-2-carboxylic acid ([3H]CGS 19755; IC50 = 67 +/- 6 nM), and selective NMDA antagonist activity was determined using a cortical slice preparation (IC50 versus 40 microM NMDA = 1.9 +/- 0.24 microM). This compound also demonstrated potent NMDA antagonist activity in vivo following systemic administration through its ability to block NMDA-induced convulsions in neonatal rats, NMDA-induced lethality in mice, and NMDA-induced striatal neuronal degeneration in rats.     

2(1H)-quinolinones with cardiac stimulant activity. 1. Synthesis and biological activities of (six-membered heteroaryl)-substituted derivatives

A series of (six-membered heteroaryl)-substituted 2(1H)-quinolinones (1) was synthesized, and structure-activity relationships for cardiac stimulant activity were determined. Most compounds were prepared by acidic hydrolysis of a heteroaryl-2-methoxyquinoline obtained by palladium-catalyzed cross-coupling methodology. Direct reaction of a pyridinylzinc reagent with a 6-haloquinolinone also proved successful. In anesthetized dogs, 6-pyridin-3-yl-2(1H)-quinolinone (3; 50 micrograms/kg) displayed greater inotropic activity (percentage increase in dP/dt max) than positional isomers (2, 4-6), and potency was maintained with either mono- (13, 15) or di- (16) alkylpyridinyl substituents. Introduction of a 4- (24) or 7- (25) methyl group into 3 reduced inotropic activity, whereas the 8-isomer (26) proved to be the most potent member of the series. Compound 26 and the 2,6-dimethylpyridinyl analogue (27) were approximately 6 and 3 times more potent than milrinone. Several quinolinones displayed positive inotropic activity (decrease in QA interval) in conscious dogs after oral administration (1 mg/kg), and 26, 27 were again the most potent members of the series. Compound 27 (0.25, 0.5, 1.0 mg/kg po) demonstrated dose-related cardiac stimulant activity, which was maintained for at least 4 h. No changes in heart rate were observed. Compounds 3, 4, 26, and 27 also selectively stimulated the force of contraction, rather than heart rate, in the dog heart-lung preparation. For a 50% increase in dP/dt max with 27, heart rate changed by less than 10 beats/min. In norepinephrine contracted rabbit femoral artery and saphenous vein, 27 produced dose related (5 X 10(-7) to 5 X 10(-4) M) vasorelaxant activity. The combined cardiac stimulant and vasodilator properties displayed by 27, coupled with a lack of effect on heart rate, should be beneficial for the treatment of congestive heart failure.     

Antidiuretic effects of a novel nonpeptide vasopressin V(2)-receptor agonist, OPC-51803, administered orally to dogs

We elucidated the pharmacological properties of a novel nonpeptide vasopressin V(2)-receptor agonist, OPC-51803 ((5R)-2-[1-(2-chloro-4-(1-pyrrolidinyl)benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-yl]-N-isopropylacetamide), via both in vitro binding experiments incorporating canine kidney and platelet membrane fractions and in vivo experiments that would determine the compound's antidiuretic effects after oral administration to water-loaded dogs. OPC-51803 displaced [(3)H]arginine vasopressin (AVP) binding to canine V(2) and V(1a) receptors, as determined by resulting K(i) values of 15.2 +/- 0.6 nM (n = 4) and 653 +/- 146 nM (n = 4), respectively. These data indicate that OPC-51803 was about 43 times more selective for V(2) receptors than for V(1a) receptors. Antidiuretic studies showed that orally administered doses of OPC-51803 (0.03 to 0.3 mg x kg(-1)) decreased urine volume and increased urinary osmolality in a dose-dependent manner in water-loaded dogs. Intravenous OPC-51803 infusions (0.3 and 3 microg x kg(-1) x min(-1)) did not affect renal or systemic hemodynamics in anesthetized dogs. Since these results confirm that OPC-51803 shows antidiuretic action in dogs, the compound may be useful for treating AVP-deficient pathophysiological states.     

Study on the effectiveness of toborinone (OPC-18790) in the treatment of heart failure in patients following cardiac surgery.

Toborinone ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-qui nolinone, CAS 128667-95-8, OPC-18790), a novel cardiotonic agent with an inhibitory action on phosphodiesterase, is known to have a potent positive inotropic action with no positive chronotropic effect. The effectiveness of this drug in the treatment of heart failure occurring immediately after extracorporeal circulation (ECC) in cardiac surgery was investigated. The study was conducted in 12 patients with valvular heart disease showing a cardiac index (CI) of below 2.8 l/min/m2 and/or pulmonary capillary wedge pressure (PCWP) or pulmonary arterial diastolic pressure (PAD) of above 8 mmHg immediately after extracorporeal circulation. In group A (n = 6), toborinone was infused at a rate of 40 micrograms/kg/min for the first 5 min and then at 10 micrograms/kg/min for 85 min. In group B (n = 6), the drug was infused at a rate of 10 micrograms/kg/min for the entire 90 min. CI, mean systemic arterial pressure (mSAP), mean pulmonary artery pressure (mPAP), CVP, PCWP, and heart rate were measured at 5, 15, 30, 60, and 90 min after the start of infusion. The infusion volume required to maintain a constant PCWP was also estimated. In group A, CI increased rapidly and significantly from the baseline of 2.48 +/- 0.23 l/min/m2 to 3.57 +/- 1.07 l/min/m2 at 5 min after the start of infusion, and at that time mSAP was slightly decreased. In group B, CI increased gradually from the baseline of 2.53 +/- 0.18 l/min/m2 to 3.08 +/- 0.34 l/min/m2 at 15 min after the start of infusion, but almost no change was seen in mSAP. During the first 30 min, group A required a significantly larger infusion volume (983 +/- 395 ml) than group B (475 +/- 184 ml). From 30 to 90 min after the start of infusion, CI remained increased to similar levels in both groups and mSAP levels were also similar. There were no significant differences between the two groups in any other parameter. Continuous infusion of toborinone appears to be effective for treating heart failure occurring immediately after ECC in cardiac surgery. Initial loading at a rate of 40 micrograms/kg/min rapidly increased CI but was accompanied by mild hypotension. Constant infusion at 10 micrograms/kg/min brought about a more gradual effect that was similar to that of loading at 40 micrograms/kg/min, but without inducing hypotension. Thus, infusion at 10 micrograms/kg/min is considered preferable in order to avoid a larger-than-necessary infusion volume.