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1.
Anal Biochem ; 568: 41-50, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30605634

RESUMO

Apelin, the endogenous ligand for the APJ receptor, has generated interest due to its beneficial effects on the cardiovascular system. Synthesized as a 77 amino acid preproprotein, apelin is post-translationally cleaved to a series of shorter peptides. Though (Pyr)1apelin-13 represents the major circulating form in plasma, it is highly susceptible to proteolytic degradation and has an extremely short half-life, making it challenging to quantify. Literature reports of apelin levels in rodents have historically been determined with commercial ELISA kits which suffer from a lack of selectivity, recognizing a range of active and inactive isoforms of apelin peptide. (Pyr)1apelin-13 has demonstrated beneficial hemodynamic effects in humans, and we wished to evaluate if similar effects could be measured in pre-clinical models. Despite development of a highly selective LC/MS/MS method, in rodent studies where (Pyr)1apelin-13 was administered exogenously the peptide was not detectable until a detailed stabilization protocol was implemented during blood collection. Further, the inherent high clearance of (Pyr)1apelin-13 required an extended release delivery system to enable chronic dosing. The ability to deliver sustained doses and stabilize (Pyr)1apelin-13 in plasma allowed us to demonstrate for the first time the link between systemic concentration of apelin and its pharmacological effects in animal models.

2.
J Med Chem ; 60(12): 5193-5208, 2017 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-28541707

RESUMO

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.


Assuntos
Artrite Experimental/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacologia , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Relação Estrutura-Atividade , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Células CACO-2/efeitos dos fármacos , Células CACO-2/imunologia , Cães , Canal de Potássio ERG1/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Coelhos
3.
J Med Chem ; 60(9): 3795-3803, 2017 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-28418664

RESUMO

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Quinazolinas/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cães , Espectrometria de Massas , Bloqueadores dos Canais de Potássio/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Quinazolinas/química , Quinazolinas/farmacologia , Coelhos , Bloqueadores dos Canais de Sódio/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
4.
Cancer Chemother Pharmacol ; 79(4): 711-723, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28283735

RESUMO

PURPOSE: Pulmonary arterial hypertension (PAH) results from occlusion or vasoconstriction of pulmonary vessels, leading to progressive right ventricular failure. Dasatinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myelogenous leukemia, has been associated with PAH. In contrast, the BCR-ABL1 TKI imatinib has demonstrated anti-vasoproliferative properties and has been investigated as a potential treatment for PAH. Here we describe studies evaluating the effects of dasatinib and imatinib on cardiovascular and pulmonary functions to understand the reported differential consequences of the two TKIs in a clinical setting. METHODS: The direct effects of dasatinib and imatinib were explored in vivo to investigate possible mechanisms of dasatinib-induced PAH. In addition, effects of dasatinib and imatinib on PAH-related mediators were evaluated in vitro. RESULTS: In rats, both TKIs increased plasma nitric oxide (NO), did not induce PAH-related structural or molecular changes in PA or lungs, and did not alter hemodynamic lung function compared with positive controls. Similarly, in the pulmonary artery endothelial cells and smooth muscle cells co-culture model, imatinib and dasatinib increased NO and decreased endothelin-1 protein and mRNA. CONCLUSIONS: The results of these studies indicated that dasatinib did not induce physiological changes or molecular signatures consistent with PAH when compared to positive controls. Instead, dasatinib induced changes consistent with imatinib. Both dasatinib and imatinib induced biochemical and structural changes consistent with a protective effect for PAH. These data suggest that other factors of unclear etiology contributed to the development of PAH in patients treated with dasatinib.


Assuntos
Antineoplásicos/toxicidade , Dasatinibe/toxicidade , Hipertensão Pulmonar/induzido quimicamente , Mesilato de Imatinib/toxicidade , Inibidores de Proteínas Quinases/toxicidade , Animais , Antineoplásicos/farmacocinética , Dasatinibe/farmacocinética , Endotelina-1/sangue , Expressão Gênica/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Hipertensão Pulmonar/fisiopatologia , Mesilato de Imatinib/farmacocinética , Pulmão/patologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/sangue , Inibidores de Proteínas Quinases/farmacocinética , Artéria Pulmonar/efeitos dos fármacos , Circulação Pulmonar/efeitos dos fármacos , RNA Mensageiro/sangue , Ratos , Ratos Sprague-Dawley
5.
Toxicol Sci ; 155(2): 348-362, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27864544

RESUMO

BMS-986094, a 2'-C-methylguanosine prodrug that was in development for treatment of chronic hepatitis C infection was withdrawn from Phase 2 clinical trials because of unexpected cardiac and renal adverse events. Investigative nonclinical studies were conducted to extend the understanding of these findings using more comprehensive endpoints. BMS-986094 was given orally to female CD-1 mice (25 and 150 mg/kg/d) for 2 weeks (53/group) and to cynomolgus monkeys (15 and 30 mg/kg/d) for up to 6 weeks (2-3/sex/group for cardiovascular safety, and 5/sex/group for toxicology). Endpoints included toxicokinetics; echocardiography, telemetric hemodynamics and electrocardiography, and tissue injury biomarkers (monkey); and light and ultrastructural pathology of heart, kidney, and skeletal muscle (mouse/monkey). Dose-related and time-dependent findings included: severe toxicity in mice at 150 mg/kg/d and monkeys at 30 mg/kg/d; decreased left ventricular (LV) ejection fraction, fractional shortening, stroke volume, and dP/dt; LV dilatation, increased QTc interval, and T-wave flattening/inversion (monkeys at ≥ 15 mg/kg/d); cardiomyocyte degeneration (mice at 150 mg/kg/d and monkeys at ≥ 15 mg/kg/d) with myofilament lysis/myofbril disassembly; time-dependent proteinuria and increased urine ß-2 microglobulin, calbindin, clusterin; kidney pallor macroscopically; and tubular dilatation (monkeys); tubular regeneration (mice 150 mg/kg/d); and acute proximal tubule degeneration ultrastructurally (mice/monkeys); and skeletal muscle degeneration with increased urine myoglobin and serum sTnI. These studies identified changes not described previously in studies of BMS-986094 including premonitory cardiovascular functional changes as well as additional biomarkers for muscle and renal toxicities. Although the mechanism of potential toxicities observed in BMS-986094 studies was not established, there was no evidence for direct mitochondrial toxicity.


Assuntos
Guanosina Monofosfato/análogos & derivados , Coração/efeitos dos fármacos , RNA Replicase/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Feminino , Guanosina Monofosfato/uso terapêutico , Guanosina Monofosfato/toxicidade , Coração/fisiologia , Hepatite C Crônica/tratamento farmacológico , Rim/efeitos dos fármacos , Macaca fascicularis , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Toxicocinética
6.
ACS Med Chem Lett ; 7(3): 283-8, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26985316

RESUMO

Clinical validation of S1P receptor modulation therapy was achieved with the approval of fingolimod (Gilenya, 1) as the first oral therapy for relapsing remitting multiple sclerosis. However, 1 causes a dose-dependent reduction in the heart rate (bradycardia), which occurs within hours after first dose. We disclose the identification of clinical compound BMS-986104 (3d), a novel S1P1 receptor modulator, which demonstrates ligand-biased signaling and differentiates from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model.

7.
J Biomol Screen ; 15(2): 185-95, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20044579

RESUMO

Voltage-gated K(+) channels are potential drug targets for an increasing number of disease indications. Searching for compounds that modulate K(+) channel activities by high-throughput screening (HTS) is becoming a standard approach in the drug discovery effort. Here the authors report an improved fluorometric imaging plate reader (FLIPR) membrane potential assay for Kv1.3 K(+) channel HTS. They have found that the Chinese hamster ovary (CHO) cells have endogenous membrane electrogenic transporters that contribute to maintaining membrane potential. Blocking the recombinant K(+) channels in the overexpressing CHO cell line hardly changed the membrane potential. Inhibition of the endogenous transporters is essential to achieve the required assay robustness. The authors identified the optimal assay conditions and designed a simple assay format. After an HTS campaign using this assay, various chemical series of Kv1.3 channel blockers have been identified and confirmed by the automated electrophysiological IonWorks assay. The correlation in dose response between FLIPR and IonWorks was established by biophysical modeling and experimental data. After characterization using patch-clamp recording, both use-dependent and use-independent compounds were identified. Some compounds possess nanomolar potency, indicating that the FLIPR assay is effective for successfully identifying K(+) channel blockers as novel drug candidates.


Assuntos
Bioensaio , Ensaios de Triagem em Larga Escala , Canal de Potássio Kv1.3/antagonistas & inibidores , Potenciais da Membrana/fisiologia , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Eletrofisiologia , Fluorometria , Concentração Inibidora 50 , Técnicas de Patch-Clamp , Azida Sódica/farmacologia
8.
J Med Chem ; 52(21): 6531-4, 2009 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-19888755

RESUMO

Atrial fibrillation is the most prevalent form of cardiac arrhythmia. Current treatments extend the atrial effective refractory period by nonselective blockade of cardiac ion channels. An alternative approach selectively targeting the Kv1.5 ion channel offers the opportunity for therapeutic benefit with decreased risk of adverse cardiovascular events. KVI-020 (4g) successfully demonstrated antiarrhythmic efficacy in a canine arrhythmia model, and these findings support its utility as an antiarrhythmic agent.


Assuntos
Antiarrítmicos/síntese química , Fibrilação Atrial/tratamento farmacológico , Imidazolidinas/síntese química , Canal de Potássio Kv1.5/antagonistas & inibidores , Sulfonamidas/síntese química , Animais , Antiarrítmicos/farmacocinética , Antiarrítmicos/farmacologia , Linhagem Celular , Cricetinae , Cricetulus , Cães , Humanos , Imidazolidinas/farmacocinética , Imidazolidinas/farmacologia , Técnicas In Vitro , Microssomos Hepáticos/metabolismo , Técnicas de Patch-Clamp , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia
9.
Circ Arrhythm Electrophysiol ; 2(2): 171-8, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19808462

RESUMO

BACKGROUND: Abnormal intercellular communication caused by connexin dysfunction may contribute to atrial fibrillation (AF). The present study assessed the effect of the gap junction conduction-enhancing antiarrhythmic peptide GAP-134 on AF inducibility and maintenance in a dog model of atrial cardiomyopathy. METHODS AND RESULTS: Twenty-four dogs subject to simultaneous atrioventricular pacing (220 bpm for 14 days) were randomly assigned to placebo treatment (PACED-CTRL; 12 dogs) or oral GAP-134 (2.9 mg/kg BID; PACED-GAP-134; 12 dogs) starting on day 0. UNPACED-CTRL (4 dogs) and UNPACED-GAP-134 (4 dogs) served as additional control groups. Change in left atrial (LA) systolic area from baseline to 14 days was calculated using transoesophageal echocardiography. At 14 days, animals underwent an open-chest electrophysiological study. PACED-CTRL dogs (versus UNPACED-CTRL) had a shorter estimated LA wavelength (8.0+/-1.4 versus 24.4+/-2.5 cm, P<0.05) and a greater AF vulnerability (mean AF duration, 1588+/-329 versus 25+/-34 seconds, P<0.05). Oral GAP-134 had no effect on AF vulnerability in UNPACED dogs. Compared with PACED-CTRL dogs, PACED-GAP-134 dogs had a longer estimated LA wavelength (10.2+/-2.8 versus 8.0+/-1.4 cm, respectively, P<0.05). Oral GAP-134 did not significantly reduce AF inducibility or maintenance in the entire group of 24 PACED dogs; in a subgroup of dogs (n=11) with less than 100% increase in LA systolic area, oral GAP-134 reduced AF induction from 100% to 40% and mean AF duration from 1737+/-120 to 615+/-280 seconds (P<0.05). CONCLUSIONS: Oral GAP-134 reduces pacing-induced decrease in LA wavelength and appears to attenuate AF vulnerability in dogs with less atrial mechanical remodeling. Gap junction modulation may affect AF in some circumstances.


Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/fisiopatologia , Benzamidas/farmacologia , Junções Comunicantes/fisiologia , Prolina/análogos & derivados , Administração Oral , Animais , Estimulação Cardíaca Artificial , Conexina 43/metabolismo , Modelos Animais de Doenças , Cães , Fibrose , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Sistema de Condução Cardíaco/efeitos dos fármacos , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/patologia , Imuno-Histoquímica , Prolina/farmacologia , Período Refratário Eletrofisiológico/efeitos dos fármacos
10.
J Cardiovasc Pharmacol Ther ; 14(3): 207-14, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19721133

RESUMO

The antiarrhythmic dipeptide, GAP-134, ([2S,4R]-1[2-aminoacetyl]-4-benzamido-pyrrolidine-2-carboxylic acid) was evaluated in canine ischemia/reperfusion model. In dogs subjected to 60-minute ischemia and 4-hour reperfusion, GAP-134 was administered 10 minutes before reperfusion as a bolus + intravenous (IV) infusion. The doses administered were 0.25 microg/kg bolus + 0.19 microg/kg per hour infusion; 2.5 microg/kg + 1.9 microg/kg per hour; 25 mg/kg + 19 mg/kg per hour; 75 mg/kg + 57 mg/kg per hour. Ventricular ectopy was quantified during reperfusion, including premature ventricular contractions (PVC) and ventricular tachycardia (VT). Total incidence of VT was reduced significantly with the 2 highest doses of GAP-134 (1.7 + 0.8; 2.2 + 1.4 events; P < .05) compared to controls (23.0 + 6.1). Total PVCs were reduced significantly from 11.1 + 1.6% in control animals to 2.0% + 0.7% and 1.8% + 0.8% after the 2 highest doses of GAP-134. Infarct size, expressed as percentage of left ventricle, was reduced significantly from 19.0% + 3.5% in controls to 7.9% + 1.5% and 7.1% + 0.8% (P < .05) at the 2 highest doses of GAP-134. GAP-134 is an effective antiarrhythmic agent with potential to reduce ischemia/reperfusion injury.


Assuntos
Antiarrítmicos/farmacologia , Benzamidas/farmacologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miocárdio/patologia , Prolina/análogos & derivados , Taquicardia Ventricular/prevenção & controle , Complexos Ventriculares Prematuros/prevenção & controle , Animais , Antiarrítmicos/administração & dosagem , Benzamidas/administração & dosagem , Circulação Coronária/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Infusões Intravenosas , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Prolina/administração & dosagem , Prolina/farmacologia , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/patologia , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo , Complexos Ventriculares Prematuros/etiologia , Complexos Ventriculares Prematuros/patologia , Complexos Ventriculares Prematuros/fisiopatologia
11.
Bioorg Med Chem Lett ; 19(16): 4551-4, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19616941

RESUMO

In an effort to discover potent, orally bioavailable compounds for the treatment of atrial fibrillation (AF) and ventricular tachycardia (VT), we developed a class of gap-junction modifiers typified by GAP-134 (1, R(1)=OH, R(2)=NH(2)), a compound currently under clinical evaluation. Selected compounds with the desired in-vitro profile demonstrated positive in vivo results in the mouse CaCl(2) arrhythmia model upon oral administration.


Assuntos
Antiarrítmicos/química , Benzamidas/química , Junções Comunicantes/efeitos dos fármacos , Prolina/análogos & derivados , Administração Oral , Animais , Antiarrítmicos/farmacocinética , Antiarrítmicos/farmacologia , Arritmias Cardíacas/tratamento farmacológico , Fibrilação Atrial/tratamento farmacológico , Benzamidas/farmacocinética , Benzamidas/farmacologia , Modelos Animais de Doenças , Cães , Descoberta de Drogas , Camundongos , Prolina/química , Prolina/farmacocinética , Prolina/farmacologia , Ratos , Relação Estrutura-Atividade , Taquicardia Ventricular/tratamento farmacológico
12.
J Pharmacol Exp Ther ; 329(3): 1127-33, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19252062

RESUMO

Gap junction uncoupling can alter conduction pathways and promote cardiac re-entry mechanisms that potentiate many supraventricular arrhythmias, such as atrial fibrillation (AF) and atrial flutter (AFL). Our objective was to determine whether GAP-134 [(2S,4R)-1-(2-aminoacetyl)-4-benzamido-pyrrolidine-2-carboxylic acid], a small dipeptide gap junction modifier, can improve conduction and ultimately prevent AF/AFL. In rat atrial strips subjected to metabolic stress, GAP-134 prevented significantly conduction velocity slowing at 10 nM compared with vehicle (p < 0.01). In the canine sterile pericarditis model, conduction time (CT; n = 5), atrial effective refractory period (AERP; n = 3), and AF/AFL duration/inducibility (n = 16) were measured 2 to 3 days postoperatively in conscious dogs. CT was significantly faster after GAP-134 infusion (average plasma concentration, 250 nM) at cycle lengths of 300 ms (66.2 +/- 1.0 versus 62.0 +/- 1.0 ms; p < 0.001) and 200 ms (64.4 +/- 0.9 versus 61.0 +/- 1.3 ms; p < 0.001). No significant changes in AERP were noted after GAP-134 infusion. The mean number of AF/AFL inductions per animal was significantly decreased after GAP-134 infusion (2.7 +/- 0.6 versus 1.6 +/- 0.8; p < 0.01), with total AF/AFL burden being decreased from 12,280 to 6063 s. Western blot experiments showed no change in connexin 43 expression. At concentrations exceeding those described in the AF/AFL experiments, GAP-134 had no effect on heart rate, blood pressure, or any electrocardiogram parameters. In conclusion, GAP-134 shows consistent efficacy on measures of conduction and AF/AFL inducibility in the canine sterile pericarditis model. These findings, along with its oral bioavailability, underscore its potential antiarrhythmic efficacy.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Flutter Atrial/tratamento farmacológico , Benzamidas/uso terapêutico , Dipeptídeos/uso terapêutico , Junções Comunicantes/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Pericardite/tratamento farmacológico , Prolina/análogos & derivados , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/fisiopatologia , Flutter Atrial/fisiopatologia , Benzamidas/farmacologia , Conexina 43/metabolismo , Dipeptídeos/efeitos adversos , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Cães , Condutividade Elétrica , Feminino , Junções Comunicantes/fisiologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Sistema de Condução Cardíaco/fisiologia , Masculino , Estrutura Molecular , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Pericardite/fisiopatologia , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/fisiopatologia , Prolina/farmacologia , Prolina/uso terapêutico , Ratos , Ratos Sprague-Dawley , Período Refratário Eletrofisiológico/efeitos dos fármacos
13.
J Med Chem ; 52(4): 908-11, 2009 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-19175320

RESUMO

Rotigaptide (3) is an antiarrhythmic peptide that improves cardiac conduction by modifying gap-junction communication. Small molecule gap-junction modifiers with improved physical properties were identified from a Zealand Pharma peptide library using pharmaceutical profiling, established SAR around 3, and a putative pharmacophore model for rotigaptide. Activity of the compounds was confirmed in a mouse cardiac conduction block model of arrhythmia. Dipeptide 9f (GAP-134) was identified as a potent, orally active gap-junction modifier for clinical development.


Assuntos
Antiarrítmicos/química , Fibrilação Atrial/tratamento farmacológico , Benzamidas/farmacologia , Junções Comunicantes/efeitos dos fármacos , Prolina/análogos & derivados , Administração Oral , Animais , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Benzamidas/química , Benzamidas/uso terapêutico , Dipeptídeos/química , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Modelos Animais de Doenças , Descoberta de Drogas , Camundongos , Biblioteca de Peptídeos , Prolina/química , Prolina/farmacologia , Prolina/uso terapêutico , Relação Estrutura-Atividade
14.
Cardiovasc Res ; 79(3): 416-26, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18430749

RESUMO

AIMS: Rotigaptide is proposed to exert its anti-arrhythmic effects by improving myocardial gap-junction communication. To directly investigate the mechanisms of rotigaptide action, we treated cultured neonatal murine ventricular cardiomyocytes with clinical pharmacological doses of rotigaptide and directly determined its effects on gap-junctional currents. METHODS AND RESULTS: Neonatal murine ventricular cardiomyocytes were enzymatically isolated and cultured for 1-4 days. Primary culture cell pairs were subjected to dual whole cell patch-clamp procedures to directly measure gap-junctional currents (I(j)) and voltage (V(j)). Rotigaptide (0-350 nM) was applied overnight or acutely perfused into 35 mm culture dishes. Rotigaptide (35-100 nM) acutely and chronically increased the resting gap-junction conductance (g(j)), and normalized steady-state minimum g(j) (G(min)) by 5-20%. Higher concentrations produced a diminishing response, which mimics the observed therapeutic efficacy of the drug. The inactivation kinetics was similarly slowed in a therapeutic concentration-dependent manner without affecting the V(j) dependence of inactivation or recovery. The effects of 0-100 nM rotigaptide on ventricular g(j) during cardiac action potential propagation were accurately modelled by computer simulations which demonstrate that clinically effective concentrations of rotigaptide can partially reverse conduction slowing due to decreases in g(j) and inactivation. CONCLUSION: These results demonstrate that therapeutic concentrations of rotigaptide increase the resting gap-junction conductance and reduce the magnitude and kinetics of steady-state inactivation in a concentration-dependent manner. Rotigaptide may be effective in treating re-entrant forms of cardiac arrhythmias by improving conduction and preventing the formation of re-entrant circuits in partially uncoupled myocardium.


Assuntos
Antiarrítmicos/farmacologia , Comunicação Celular/efeitos dos fármacos , Junções Comunicantes/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Potenciais de Ação , Animais , Animais Recém-Nascidos , Células Cultivadas , Simulação por Computador , Relação Dose-Resposta a Droga , Junções Comunicantes/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Modelos Cardiovasculares , Miócitos Cardíacos/metabolismo
15.
J Pharmacol Exp Ther ; 324(2): 497-506, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18024786

RESUMO

P-selectin plays a significant and well documented role in vascular disease by mediating leukocyte and platelet rolling and adhesion. This study characterizes the in vitro activity, pharmacokinetic properties, and the anti-inflammatory and antithrombotic efficacy of the orally active P-selectin small-molecule antagonist PSI-697 [2-(4-chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[h] quinoline-4-carboxylic acid; molecular mass, 367.83]. Biacore and cell-based assays were used to demonstrate the ability of PSI-697 to dose dependently inhibit the binding of human P-selectin to human P-selectin glycoprotein ligand-1, inhibiting 50% of binding at 50 to 125 microM. The pharmacokinetics of PSI-697 in rats were characterized by low clearance, short half-life, low volume of distribution, and moderate apparent oral bioavailability. A surgical inflammation model, using exteriorized rat cremaster venules, demonstrated that PSI-697 (50 mg/kg p.o.) significantly reduced the number of rolling leukocytes by 39% (P < 0.05) versus vehicle control. In a rat venous thrombosis model, PSI-697 (100 mg/kg p.o.) reduced thrombus weight by 18% (P < 0.05) relative to vehicle, without prolonging bleeding time. Finally, in a rat carotid injury model, PSI-697 (30 or 15 mg/kg p.o.) administered 1 h before arterial injury and once daily thereafter for 13 days resulted in dose-dependent decreases in intima/media ratios of 40.2% (P = 0.025) and 25.7% (P = 0.002) compared with vehicle controls. These data demonstrate the activity of PSI-697 in vitro and after oral administration in animal models of both arterial and venous injury and support the clinical evaluation of this novel antagonist of P-selectin in atherothrombotic and venous thrombotic indications.


Assuntos
Modelos Animais de Doenças , Hidroxiquinolinas/uso terapêutico , Selectina-P , Vasculite/tratamento farmacológico , Trombose Venosa/tratamento farmacológico , Animais , Células HL-60 , Humanos , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Masculino , Selectina-P/metabolismo , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Vasculite/metabolismo , Trombose Venosa/metabolismo
16.
Basic Clin Pharmacol Toxicol ; 101(4): 215-30, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17845503

RESUMO

Existing anti-arrhythmic therapy is hampered by lack of efficacy and unacceptable side effects. Thus, ventricular tachycardia and fibrillation remains the strongest predictor of in-hospital mortality in patients with myocardial infarction. In atrial fibrillation, rhythm control with conventional ion channel blockers provide no therapeutic benefit relative to rate control. Several lines of research indicate that impaired gap junctional cell-to-cell coupling between neighbouring cardiomyocytes is critical for the development of cardiac re-entry arrhythmias. Rotigaptide is the first drug that has been developed to prevent arrhythmias by re-establishing gap junctional intercellular communication. During conditions with acute cardiac ischaemia, rotigaptide effectively prevents induction of both ventricular and atrial tachyarrhythmia. Moreover, rotigaptide effectively prevents ischaemia reperfusion arrhythmias. At the cellular level, rotigaptide inhibits ischaemia-induced dephosphorylation of Ser297 and Ser368, which is considered important for the gating of connexin43 gap junction channels. No drug-related toxicity has been demonstrated at plasma concentrations 77,000 times above therapeutic concentrations. In rats and dogs, rotigaptide reduces infarct size following myocardial infarction. A series of phase I trials has been completed in which rotigaptide has been administered intravenously to ~200 healthy persons. No drug-related side effects have been demonstrated in healthy human beings. Clinical safety, tolerability and efficacy in patients with heart disease are being evaluated in ongoing clinical trials. Rotigaptide represents a pioneering pharmacological principle with a highly favourable preclinical and clinical safety profile, which makes this molecule a promising drug candidate for the prevention of cardiac arrhythmias.


Assuntos
Antiarrítmicos , Arritmias Cardíacas/prevenção & controle , Junções Comunicantes/efeitos dos fármacos , Oligopeptídeos , Animais , Antiarrítmicos/efeitos adversos , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/fisiopatologia , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/prevenção & controle , Junções Comunicantes/fisiologia , Humanos , Oligopeptídeos/efeitos adversos , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/prevenção & controle
17.
J Membr Biol ; 216(1): 23-35, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17568971

RESUMO

Much of our current knowledge about the physiological and pathophysiological role of gap junctions is based on experiments where coupling has been reduced by either chemical agents or genetic modification. This has brought evidence that gap junctions are important in many physiological processes. In a number of cases, gap junctions have been implicated in the initiation and progress of disease, and experimental uncoupling has been used to investigate the exact role of coupling. The inverse approach, i.e., to increase coupling, has become possible in recent years and represents a new way of testing the role of gap junctions. The aim of this review is to summarize the current knowledge obtained with agents that selectively increase gap junctional intercellular coupling. Two approaches will be reviewed: increasing coupling by the use of antiarrhythmic peptide and its synthetic analogs and by interfering with the gating of gap junctional channels.


Assuntos
Antiarrítmicos/farmacologia , Comunicação Celular/fisiologia , Junções Comunicantes/fisiologia , Oligopeptídeos/fisiologia , Animais , Arritmias Cardíacas/fisiopatologia , Fibrilação Atrial/fisiopatologia , Osso e Ossos/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Conexina 43/fisiologia , Feminino , Junções Comunicantes/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Isquemia Miocárdica/fisiopatologia , Oligopeptídeos/farmacologia , Osteoblastos/efeitos dos fármacos
18.
J Cardiovasc Pharmacol Ther ; 12(1): 69-77, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17495260

RESUMO

The gap junction modifier Rotigaptide (ZP123), which promotes cellular coupling, was hypothesized to decrease defibrillation thresholds during prolonged ventricular fibrillation (VF). Thirty-two New Zealand white rabbits were randomized to receive saline (control, n = 16) or Rotigaptide (n = 16). Following 4 min of untreated VF, biphasic defibrillation shocks were applied through chest wall patches, starting either at 300 volts (V) (n = 16) or 500 V (n = 16), with 200 V increasing steps to 900 V in case of shock failure. Rotigaptide significantly decreased defibrillation voltage requirements (average cumulative voltage of all shocks: 1206 +/- 709 V in control group vs. 844 +/- 546 V in treated group, P = .002). Rotigaptide had no effect on heart rate, QRS duration, QT interval, ventricular effective refractory period, monophasic action potential duration or on connexin 43 density using immunofluorescence. Rotigaptide improves the ability to defibrillate after untreated VF.


Assuntos
Junções Comunicantes/efeitos dos fármacos , Parada Cardíaca/terapia , Oligopeptídeos/uso terapêutico , Fibrilação Ventricular/terapia , Potenciais de Ação/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Conexina 43/metabolismo , Modelos Animais de Doenças , Cardioversão Elétrica/métodos , Estimulação Elétrica/métodos , Eletrocardiografia , Imunofluorescência/métodos , Junções Comunicantes/fisiologia , Parada Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Injeções Intravenosas , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/metabolismo , Oligopeptídeos/administração & dosagem , Oligopeptídeos/sangue , Coelhos , Distribuição Aleatória , Ressuscitação/métodos , Fibrilação Ventricular/fisiopatologia
19.
Circulation ; 115(3): 310-8, 2007 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-17224477

RESUMO

BACKGROUND: Abnormal intercellular communication caused by connexin dysfunction may be involved in atrial fibrillation (AF). The present study assessed the effect of the gap junctional conduction-enhancing peptide rotigaptide on AF maintenance in substrates that result from congestive heart failure induced by 2-week ventricular tachypacing (240 bpm), atrial tachypacing (ATP; 400 bpm for 3 to 6 weeks), and isolated atrial myocardial ischemia. METHODS AND RESULTS: Electrophysiological study and epicardial mapping were performed before and after rotigaptide administration in dogs with ATP and congestive heart failure, as well as in similarly instrumented sham dogs that were not tachypaced. For atrial myocardial ischemia, dogs administered rotigaptide before myocardial ischemia were compared with no-drug myocardial ischemia controls. ATP significantly shortened the atrial effective refractory period (P=0.003) and increased AF duration (P=0.008), with AF lasting >3 hours in all 6-week ATP animals. Rotigaptide increased conduction velocity in ATP dogs slightly but significantly (P=0.04) and did not affect the effective refractory period, AF duration, or atrial vulnerability. In dogs with congestive heart failure, rotigaptide also slightly increased conduction velocity (P=0.046) but failed to prevent AF promotion. Rotigaptide had no statistically significant effects in sham dogs. Myocardial ischemia alone increased AF duration and impaired conduction (based on conduction velocity across the ischemic border and indices of conduction heterogeneity). Rotigaptide prevented myocardial ischemia-induced conduction slowing and AF duration increases. CONCLUSIONS: Rotigaptide improves conduction in various AF models but suppresses AF only for the acute ischemia substrate. These results define the atrial antiarrhythmic profile of a mechanistically novel antiarrhythmic drug and suggest that gap junction dysfunction may be more important in ischemic AF than in ATP remodeling or congestive heart failure substrates.


Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/fisiopatologia , Junções Comunicantes/efeitos dos fármacos , Sistema de Condução Cardíaco/efeitos dos fármacos , Oligopeptídeos/farmacologia , Animais , Antiarrítmicos/sangue , Antiarrítmicos/uso terapêutico , Fibrilação Atrial/prevenção & controle , Modelos Animais de Doenças , Cães , Eletrocardiografia , Eletrofisiologia , Junções Comunicantes/fisiologia , Sistema de Condução Cardíaco/fisiologia , Insuficiência Cardíaca/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Oligopeptídeos/sangue , Oligopeptídeos/uso terapêutico , Taquicardia Atrial Ectópica/fisiopatologia
20.
Pharmacology ; 78(1): 27-37, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16899991

RESUMO

This study examines the cardioprotective effects of Na+/H+ exchange inhibition with BIIB-722 or ischemic preconditioning after occlusive thrombus formation and subsequent thrombolysis for reperfusion. Coronary artery thrombosis was induced by vessel wall electrolytic injury. Thrombotic occlusion was maintained for 60 or 90 min in 4 different groups: (1) control; (2) Na+/H+ exchange inhibitor, BIIB-722 (3 mg/kg) before occlusion; (3) BIIB-722 (0.75 mg/kg) before reperfusion; (4) ischemic preconditioning (4 x 5 min). Thrombolysis with intracoronary recombinant tissue plasminogen activator produced reperfusion in 6.3 +/- 1.4 min (average for 68 dogs). After restoration of blood flow, vessel patency was maintained for 4 h with the glycoprotein IIb/IIIa receptor antagonist, BIBU 52ZW. BIIB-722, administered before (26.9 +/- 3.6%) or after (22.0 +/- 2.3%) 60-min ischemia or preconditioning (18.4 +/- 2.8%), produced comparable and significant reductions in infarct size (percent of area at risk) compared to controls (47.2 +/- 2.0%). After 90 min of ischemia, BIIB-722 administered before occlusion (37.3 +/- 1.1%) and ischemic preconditioning (35.0 +/- 4.8%) provided significant cardioprotection compared to control (45.9 +/- 1.8%). BIIB-722 was not cardioprotective when administered during occlusion (48.0 +/- 2.4%). The results indicate that Na+/H+ exchange inhibition and preconditioning provide a comparable degree of cardioprotection against 60 min of regional ischemia. However, when the regional ischemic period is extended to 90 min, the degree of cardioprotection is markedly reduced. Further studies incorporating clinically relevant events such as thrombosis and thrombolysis are required before one can conclude that Na+/H+ exchange inhibition is effective against more prolonged myocardial ischemia.


Assuntos
Vasos Coronários/patologia , Infarto do Miocárdio/patologia , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Terapia Trombolítica , Trombose/patologia , Animais , Cães
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