4'-[(4-Piperidyl)carbonyl]methanesulfonanilides as potent, selective, bioavailable class III antiarrhythmic agents

Oinuma, Hitoshi; Miyake, Kazutoshi; Yamanaka, M.; Nomoto, Ken’ichi; Katoh, Hiroshi; Sawada, Kohei; Shino, Mitsumasa; Hamano, Sachiyuki

doi:10.1021/jm00165a003

Cited by 17 publications

(13 citation statements)

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“…These compounds were shown not to possess any P-blocking ability and to be approximately 10 times more potent than sotalol in prolonging the action potential duration (APD) in canine Purkinje fibres. Subsequently, E-4031 (Oinuma et al, 1990) was developed by Eisai Tsukuba Research Laboratories and even more recently UK-68,798 by Pfizer (Cross et al, 1990;Gwilt et al, 1991). This latter compound has been reported to prolong APD in the concentration range 5 nM-1 ILM and is the most potent compound that has been described to date.…”

Section: Introductionmentioning

confidence: 99%

Actions and mechanisms of action of novel analogues of sotalol on guinea‐pig and rabbit ventricular cells

Connors

Gill

Terrar

1992

British J Pharmacology

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1 The actions and mechanisms of action of novel analogues of sotalol which prolong cardiac action potentials were investigated in guinea-pig and rabbit isolated ventricular cells. 2 In guinea-pig and rabbit cells the compounds significantly prolonged action potential duration at 20% and 90% repolarization levels without affecting resting membrane potential. In guinea-pig but not rabbit cells there was an increase in action potential amplitude and in rabbit cells there was no change in the shape or position of the 'notch' in the action potential. 3 Possible mechanisms of action were studied in more detail in the case of compound II (1-(4-methanesulphonamidophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol). Prolongation of action potential duration continued to occur in the presence of nisoldipine, and calcium currents recorded under voltage-clamp conditions were not reduced by compound II (1 pM). Action potential prolongation by compound II was also unaffected in the presence of 10 JiM tetrodotoxin.4 Compound II (1 !M) did not influence IKI assessed from the current during ramp changes in membrane potential (20 mV s') over the range -90 to -10 mV.5 Compound II (1 JLM) blocked time-dependent delayed rectifier potassium current (IK) activated by step depolarizations and recorded as an outward tail following repolarization. When a submaximal concentration (50 nM) was applied there was no change in the apparent reversal potential of IK-6 Submaximal concentrations of compound II were without effect on activation of IK with time at a membrane potential of + 40 mV, and no changes were detected in the time constants of the two components of IK decay over the range of potentials -60 to 0 mV. Compound 11 (50 nM) appeared to cause a small shift in the activation of IK with membrane potential (an apparent shift of approximately 10 mV in the depolarizing direction at the mid-point of the curve). 7 Log dose-response curves for action potential prolongation and for blockade of IK by compound II were similar. The IC50 for compound II was approximately 30 nM. 8 It is concluded that this novel series of compounds prolongs action potential duration, and that in the case of compound II the evidence supports a potent selective effect on the time-dependent potassium current IK, an effect which can account for this prolongation.

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Section: Introductionmentioning

confidence: 99%

Actions and mechanisms of action of novel analogues of sotalol on guinea‐pig and rabbit ventricular cells

Connors

Gill

Terrar

1992

British J Pharmacology

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“…The Neural Network (NN) is a suitable concept to achieve this goal. Several studies of QSAR have indeed been fulfilled using NN [26][27][28][29].…”

Section: Neural Networkmentioning

confidence: 99%

Quantitative Structure-Activity Relationships of Noncompetitive Antagonists of the NMDA Receptor: A Study of a Series of MK801 Derivative Molecules Using Statistical Methods and Neural Network

Elhallaoui

Elasri

Ouazzani

et al. 2003

IJMS

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From a series of 50 MK801 derivative molecules, a selected set of 44 compounds was submitted to a principal components analysis (PCA), a multiple regression analysis (MRA), and a neural network (NN). This study shows that the compounds' activity correlates reasonably well with the selected descriptors encoding the chemical structures.The correlation coefficients calculated by MRA and there after by NN, r = 0.986 and r = 0.974 respectively, are fairly good to evaluate a quantitative model, and to predict activity for MK801 derivatives. To test the performance of this model, the activities of the remained set of 6 compounds are deduced from the proposed quantitative model, by NN. This study proved that the predictive power of this model is relevant.

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“…activity and no p-blocking effects were developed and E-4031, i.e., [1-(2(6-methyl-2pyridil)ethyl)-(4-methanesulfonamidobenzoyl) piperidine], was synthesized ( Fig. 1) (14). E-4031 is a white crystalline solid with a molecular weight of 510.47.…”

Section: At Eisai Laboratories Bioavailable Methanesulfonanilide Analmentioning

confidence: 99%

“…E-4031 is a novel class I11 antimhythmic agent with structural similarity to the methanesulfonanilide group of d-sotalol(l4). In animal experiments electrophysiological studies demonstrated that E-403 1 prolonged both action potential duration and effective refractory period without changing the maximum rate of depolarization of the action potential (14,26). In isolated cat ventricular myocytes E-4031 selectively blocked the delayed rectifier potassium current (I,) (5).…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological Effects of E‐4031, A Novel Class III Antiarrhythmic Agent

Fujiki

1994

Cardiovascular Drug Reviews

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4'-[(4-Piperidyl)carbonyl]methanesulfonanilides as potent, selective, bioavailable class III antiarrhythmic agents

Cited by 17 publications

References 0 publications

Actions and mechanisms of action of novel analogues of sotalol on guinea‐pig and rabbit ventricular cells

Actions and mechanisms of action of novel analogues of sotalol on guinea‐pig and rabbit ventricular cells

Quantitative Structure-Activity Relationships of Noncompetitive Antagonists of the NMDA Receptor: A Study of a Series of MK801 Derivative Molecules Using Statistical Methods and Neural Network

Electrophysiological Effects of E‐4031, A Novel Class III Antiarrhythmic Agent

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