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1.
Life Sci ; 90(15-16): 607-11, 2012 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-22406079

RESUMO

AIMS: In a previous study we found that A-935142 enhanced hERG current in a concentration-dependent manner by facilitating activation, reducing inactivation, and slowing deactivation (Su et al., 2009). A-935142 also shortened action potential duration (APD90) in canine Purkinje fibers and guinea pig atrial tissue. This study focused on the combined effects of the prototypical hERG enhancer, A-935142 and two hERG current blockers (sotalol and terfenadine). MAIN METHODS: The whole-cell voltage clamp method with HEK 293 cells heterologously expressing the hERG channel (Kv 11.1) was used. KEY FINDINGS: A-935142 did not compete with 3H-dofetilide binding, suggesting that A-935142 does not overlap the binding site of typical hERG blockers. In whole-cell voltage clamp studies we found: 1) 60 µM A-935142 enhanced hERG current in the presence of 150 µM sotalol (57.5±5.8%) to a similar extent as seen with A-935142 alone (55.6±5.1%); 2) 150 µM sotalol blocked hERG current in the presence of 60 µM A-935142 (43.5±1.5%) to a similar extent as that seen with sotalol alone (42.0±3.2%) and 3) during co-application, hERG current enhancement was followed by current blockade. Similar results were obtained with 60 nM terfenadine combined with A-935142. SIGNIFICANCE: These results suggest that the hERG enhancer, A-935142 does not compete with these two known hERG blockers at their binding site within the hERG channel. This selective hERG current enhancement may be useful as a treatment for inherited or acquired LQTS (Casis et al., 2006).


Assuntos
Acetatos/metabolismo , Canais de Potássio Éter-A-Go-Go/metabolismo , Pirazóis/metabolismo , Análise de Variância , Células HEK293 , Humanos , Técnicas de Patch-Clamp , Fenetilaminas/metabolismo , Sotalol/farmacologia , Sulfonamidas/metabolismo , Terfenadina/farmacologia , Trítio
2.
J Pharmacol Toxicol Methods ; 64(1): 68-73, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21440075

RESUMO

INTRODUCTION: Delayed cardiac repolarization is an established risk factor for proarrhythmia and Torsades-de-Pointes (TdeP) that is typically measured in vitro during slow, regular stimulation. We have developed an alternative, novel, and rapid cellular-based approach for predicting drug-induced proarrhythmia that detects changes in electrical refractoriness based on mechanical responses (measured optically) during increasingly rapid trains of stimulation interspersed with pauses (mimicking the clinically observed short-long-short (SLS) stimulation sequence associated with the TdeP initiation). METHODS: Acutely isolated rabbit ventricular myocytes were superfused and electrically stimulated using an accelerating pacing protocol (APP) consisting of 12 consecutive pacing segments (10 beats per segment) with incrementally faster cycle lengths; trains were separated by pauses to identify loss of stimulus capture as well as to mimic clinically observed SLS sequences. Drug effects were evaluated based on a myocyte's ability to contract during progressively faster pacing segments (rate-adaptation); the earliest rate during which the myocyte fails to respond (longest cycle length with incomplete capture (CLIC)) was used to quantify electrophysiologic effects. RESULTS: Torsadogenic drugs known to delay repolarization during slow stimulation prolonged CLIC and dramatically limited the ability to respond to progressively rapid stimulation. The recognized proarrhythmic compounds E-4031, cisapride, grepafloxacin, and haloperidol rapidly prolonged CLIC at and above therapeutic concentrations in a concentration-dependent manner, while negative controls (captopril, indomethacin, and loratidine) do not affect rate-adaptation. DISCUSSION: Ventricular rate adaptation represents a novel approach for rapidly detecting drugs with torsadogenic risk using rapid rhythms that are typically not employed when evaluating proarrhythmic risk. This method is well suited for detecting and avoiding potential cardiac liabilities early in drug discovery ("frontloading") prior to final selection of candidate drugs.


Assuntos
Eletrocardiografia/efeitos dos fármacos , Coração/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/diagnóstico , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Estimulação Elétrica/métodos , Feminino , Coração/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Coelhos , Torsades de Pointes/fisiopatologia
3.
Biochem Pharmacol ; 77(8): 1383-90, 2009 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-19426677

RESUMO

Activators of the human ether-a-go-go-related gene (hERG) K(+) channel have been reported recently to enhance hERG current amplitude (five synthetic small molecules and one naturally occurring substance). Here, we characterize the effects of a novel compound A-935142 ({4-[4-(5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]-cyclohexyl}-acetic acid) on guinea-pig atrial and canine ventricular action potentials (microelectrode techniques) and hERG channels expressed in HEK-293 cells (whole-cell patch clamp techniques). A-935142 shortened cardiac action potentials and enhanced the amplitude of the hERG current in a concentration- and voltage-dependent manner. The fully activated current-voltage relationship revealed that this compound (60 microM) increased both outward and inward K(+) current as well as the slope conductance of the linear portion of the fully activated I-V relation. A-935142 significantly reduced the time constants (tau) of hERG channel activation at two example voltages (-10 mV: tau=100+/-17 ms vs. 164+/-24 ms, n=6, P<0.01; +30 mV: tau=16.7+/-1.8 ms vs. 18.9+/-1.8 ms, n=5, P<0.05) and shifted the voltage-dependence for hERG activation in the hyperpolarizing direction by 9 mV. The time course of hERG channel deactivation was slowed at multiple potentials (-120 to -70 mV). A-935142 also reduced the rate of inactivation and shifted the voltage-dependence of inactivation in the depolarizing direction by 15 mV. Recovery of hERG channel from inactivation was not affected by A-935142. In conclusion, A-935142 enhances hERG current in a complex manner by facilitation of activation, reduction of inactivation, and slowing of deactivation, and abbreviates atrial and ventricular repolarization.


Assuntos
Acetatos/farmacologia , Potenciais de Ação/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Pirazóis/farmacologia , Acetatos/química , Animais , Técnicas de Cultura de Células , Linhagem Celular , Cães , Relação Dose-Resposta a Droga , Cobaias , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Humanos , Estrutura Molecular , Técnicas de Patch-Clamp , Ramos Subendocárdicos/efeitos dos fármacos , Ramos Subendocárdicos/metabolismo , Pirazóis/química , Transfecção
4.
J Med Chem ; 50(9): 2011-29, 2007 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-17425296

RESUMO

The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 microM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.


Assuntos
Alcinos/síntese química , Antineoplásicos/síntese química , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Indenos/síntese química , Pirazóis/síntese química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tiofenos/síntese química , Alcinos/efeitos adversos , Alcinos/farmacologia , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Ligação Competitiva , Linhagem Celular , Canal de Potássio ERG1 , Edema/induzido quimicamente , Edema/tratamento farmacológico , Estradiol , Canais de Potássio Éter-A-Go-Go/fisiologia , Feminino , Humanos , Indenos/efeitos adversos , Indenos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Técnicas de Patch-Clamp , Ligação Proteica , Pirazóis/efeitos adversos , Pirazóis/metabolismo , Pirazóis/farmacologia , Ensaio Radioligante , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/metabolismo , Tiofenos/farmacologia , Doenças Uterinas/induzido quimicamente , Doenças Uterinas/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Bioorg Med Chem Lett ; 17(8): 2365-71, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17350253

RESUMO

A series of potent 2-carboxychromone-based melanin-concentrating hormone receptor 1 (MCHr1) antagonists were synthesized and evaluated for hERG (human Ether-a-go-go Related Gene) channel affinity and functional blockade. Basic dialkylamine-terminated analogs were found to weakly bind the hERG channel and provided marked improvement in a functional patch-clamp assay versus previously reported antagonists of the series.


Assuntos
Amidas/farmacologia , Cromonas/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Obesidade/tratamento farmacológico , Técnicas de Patch-Clamp , Farmacocinética
6.
Bioorg Med Chem Lett ; 17(4): 874-8, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17234405

RESUMO

The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.


Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Alquilação , Animais , Fenômenos Químicos , Físico-Química , Cromonas , Reações Cruzadas , Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Canais de Potássio Éter-A-Go-Go/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Humanos , Camundongos , Relação Estrutura-Atividade
7.
J Med Chem ; 49(22): 6569-84, 2006 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-17064075

RESUMO

Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.


Assuntos
Benzodioxóis/farmacologia , Doenças Cardiovasculares/induzido quimicamente , Cromonas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Acilação , Animais , Área Sob a Curva , Benzodioxóis/farmacocinética , Benzodioxóis/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular , Cromonas/farmacocinética , Cromonas/toxicidade , Cães , Eletrocardiografia/efeitos dos fármacos , Feminino , Meia-Vida , Frequência Cardíaca/efeitos dos fármacos , Indicadores e Reagentes , Camundongos , Camundongos Endogâmicos C57BL , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
8.
Bioorg Med Chem ; 11(22): 4769-77, 2003 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-14556792

RESUMO

The human immunodeficiency virus (HIV) has been shown to be the causative agent for AIDS. The HIV virus encodes for a unique aspartyl protease that is essential for the production of enzymes and proteins in the final stages of maturation. Protease inhibitors have been useful in combating the disease. The inhibitors incorporate a variety of isosteres including the hydroxyethylurea at the protease cleavage site. We have shown that the replacement of t-butylurea moiety by benzothiazolesulfonamide provided inhibitors with improved potency and antiviral activities. Some of the compounds have shown good oral bioavailability and half-life in rats. The synthesis of benzothiazole derivatives led us to explore other heterocycles. During the course of our studies, we also developed an efficient synthesis of benzothiazole-6-sulfonic acid via a two-step procedure starting from sulfanilamide.


Assuntos
Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Ureia/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacocinética , Humanos , Concentração Inibidora 50 , Ratos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Tiazóis/síntese química , Tiazóis/farmacocinética , Ureia/química , Ureia/farmacologia
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