Falipamil (AQ‐A 39) and UL‐FS 49

Kobinger, W.; Lillie, Christian

doi:10.1111/j.1527-3466.1988.tb00371.x

Cited by 18 publications

(8 citation statements)

References 28 publications

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“…However, the significance of action potential prolongation in the antiarrhythmic action of zatebradine may be debatable. The limited increase in QTc observed in the anesthetized rabbit and the abolition of the QT interval prolongation induced by zatebradine during atrial pacing provides confirmation of the limited class III effect of zatebradine in com parison with other specific bradycardic agents such as falipamil [3],…”

Section: Discussionmentioning

confidence: 86%

“…1), zatebradine exerts cal cium antagonistic activity on the myocar dium at a dose much higher than that respon sible for slowing heart rate [3]. In isolated car diac tissues, zatebradine has been shown to induce a frequency-dependent reduction in the diastolic depolarization resulting from a blockade of the pacemaker current of sinus node cells [14], In animal experiments, zate bradine induced a pronounced bradycardia associated with a slight prolongation of the QT interval of the electrocardiogram [7],…”

Section: Zatebradine Introductionmentioning

confidence: 99%

“…Specific bradycardic agents represent a new class of compounds with anti-ischemic properties related to a reduction in oxygen demand and an increase in coronary perfu sion during the diastole [3,4], By slowing heart rate, these compounds may also im prove subendocardial blood flow in the isch emic myocardium [5]. It has also been sug gested that specific bradycardic agents may represent a fifth class of antiarrhythmic agents [6].…”

Section: Zatebradine Introductionmentioning

confidence: 99%

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Effect of Zatebradine, a Specific Bradycardic Agent, on Ischemia-Induced Arrhythmias in Anesthetized Rabbits

Bril¹,

Forest²,

Cheval³

et al. 1994

Pharmacology

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The effects of the specific bradycardic agent, zatebradine (UL·FS 49), on ventricular arrhythmias occurring during an acute ischemia were compared to those of verapamil. Anesthetized rabbits were submitted to a ligation of the left circumflex coronary artery for 20 min. Zatebradine (150 and 750 µg/kg, i.v.) dose-dependently reduced heart rate, but changed neither the left ventricular pressure nor the (+)dp/dt_max. In comparison, verapamil (150 and 750 µg/kg, i.v.) reduced heart rate, systemic blood pressure, left ventricular pressure and (+)dp/dt_max. The incidence of ventricular premature beats occurring during acute ischemia was changed neither by zatebradine nor by verapamil. Ventricular fibrillation, occurring in 36% of the saline-treated rabbits, was reduced to 18% in the presence of 750 µg/kg of zatebradine and 0% with verapamil (750 µg/kg, p < 0.05). The action of zatebradine on ischemia-induced ventricular fibrillation, albeit limited, was completely reversed by atrial pacing to the predrug heart rate. To further investigate the mechanisms involved in the antiarrhythmic potential of both zatebradine and verapamil, their electrophysiological actions were compared in canine Purkinje fibers. Both zatebradine and verapamil induced a dose-dependent increase in action potential duration (APD) measured at 90% repolarization. The APDs measured during the plateau level (APD30) and at 50% of the repolarization (APD50) were shortened by verapamil and increased by zatebradine showing that at the concentrations used, zatebradine did not exhibit any calcium antagonistic activity when compared to verapamil. The results of the present study suggest that the specific bradycardic agent zatebradine showed a beneficial action mainly because of its anti-ischemic properties. However, the present studies performed in anesthetized rabbits suggest that in this species pure reduction in heart rate is not sufficient to entirely prevent ischemic arrhythmias.

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Section: Discussionmentioning

confidence: 86%

Section: Zatebradine Introductionmentioning

confidence: 99%

Section: Zatebradine Introductionmentioning

confidence: 99%

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Effect of Zatebradine, a Specific Bradycardic Agent, on Ischemia-Induced Arrhythmias in Anesthetized Rabbits

Bril¹,

Forest²,

Cheval³

et al. 1994

Pharmacology

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“…Thus, due to heart rate reduction they not only decrease oxygen demand but also increase oxygen supply to the ischemic myocardium via an increase in the diastolic blood flow (5,10). Alinidin and falipamil, derivatives of clonidine and verapamil, respectively, were the first compounds of this class followed by zatebradine (11,12), a more potent, longer acting, and more specific benzazepinone derivative of falipamil (13). Due to certain side effects including hypotension, negative inotropism or visual disorder (14)(15)(16), or insufficient efficacy the clinical development of these drugs was terminated (15,16).…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetic Data Analysis of Cilobradine, an If Channel Blocker

Fliss¹,

Staab²,

Tillmann³

et al. 2007

Pharm Res

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“…Amrinone (98) Anipamil ( 15) AR-12-456 (94) AR-12-463 (94) Baclofen (39) Benidipine (69) N-Benzylhydrylpiperazines (4 I ) Bepridil ( 184) Suloctidil ( 19) Tabernanthine (42) Tanshinone ( 1 18) Tiapamil (30) Urotensin I (61) Valperinol (29) Veraoamil (34) UL-FS-49 (71) , I…”

mentioning

confidence: 99%

Experimental Pharmacology of the Methylenedioxyindenes

Rahwan

1989

Cardiovascular Drug Reviews

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Calcium antagonists represent the most important addition to the therapeutic armamentarium for the treatment of cardiovascular diseases since the advent of the padrenergic receptor blocking drugs. Based on their cellular site of action, the calcium antagonists are broadly classified into two groups ( 13 1): the calcium channel blockers and the intracellular calcium antagonists. While the list of calcium channel blockers is expanding at a very rapid pace (Table I), that of intracellular calcium antagonists is relatively limited ( Table 2). Numerous recent reviews have been published on the calcium channel blockers (34,62,168), but only a few dealt with the intracellular calcium antagonists (62,13 l). While calcium channel blockers exert their pharmacological actions primarily by limiting calcium entry into cardiac or vascular smooth muscle cells, the intracellular calcium antagonists exert their actions by blocking intracelMar calcium receptors (e.g., troponin or calmodulin), preventing calcium mobilization from intracellular stores, facilitating calcium sequestration by intracellular organelles, enhancing calcium efflux from the cell, or interfering with the contractile proteins (1 3 1). The present review focuses on the methylenedioxyindenes (MDIs), a group of tertiary amine intracellular calcium antagonists developed in our laboratory (U.S. patents #4393226 and #4542153). The MDIs fulfill most of the criteria ( 13 I ) that qualify an agent to be classified primarily as an intracellular calcium antagonist. The MDIs inhibit the mobilization of calcium from the sarcoplasmic reticulum and preserve mitochondria1 structural and functional integrity against swelling and uncoupling of oxidative phosphorylation ( 132). DISCOVERY OF THE MDIsSerendipity and traditional pharmacological approaches contributed to the development of the MDIs. The MDIs were synthesized as intermediates (178) for the chemical synthesis of dibenzyloxyindanpropionic acids [DIPA (1 77)J (Fig. 1 ), in a research effort aimed at developing antiabortifacient prostaglandin FZa receptor antagonists, an endeavor that was ultimately successful (1 39). The intermediate MDIs

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Falipamil (AQ‐A 39) and UL‐FS 49

Cited by 18 publications

References 28 publications

Effect of Zatebradine, a Specific Bradycardic Agent, on Ischemia-Induced Arrhythmias in Anesthetized Rabbits

Effect of Zatebradine, a Specific Bradycardic Agent, on Ischemia-Induced Arrhythmias in Anesthetized Rabbits

Population Pharmacokinetic Data Analysis of Cilobradine, an If Channel Blocker

Experimental Pharmacology of the Methylenedioxyindenes

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