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1.
Eur J Pharmacol ; 684(1-3): 87-94, 2012 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-22504024

RESUMO

Histamine H(3) receptor antagonists have been widely reported to improve performance in preclinical models of cognition, but more recently efficacy in pain models has also been described. Here, A-960656 ((R)-2-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yl)pyridazin-3(2H)-one) was profiled as a new structural chemotype. A-960656 was potent in vitro in histamine H(3) receptor binding assays (rat K(i)=76 nM, human K(i)=21 nM), and exhibited functional antagonism in blocking agonist-induced [(35)S]GTPγS binding (rat H(3) K(b)=107 nM, human H(3) K(b)=22 nM), and was highly specific for H(3) receptors in broad screens for non-H(3) sites. In a spinal nerve ligation model of neuropathic pain in rat, oral doses of 1 and 3mg/kg were effective 60 min post dosing with an ED(50) of 2.17 mg/kg and a blood EC(50) of 639 ng/ml. In a model of osteoarthritis pain, oral doses of 0.1, 0.3, and 1mg/kg were effective 1h post dosing with an ED(50) of 0.52 mg/kg and a blood EC(50) of 233 ng/ml. The antinociceptive effect of A-960656 in both pain models was maintained after sub-chronic dosing up to 12 days. A-960656 had excellent rat pharmacokinetics (t(1/2)=1.9h, 84% oral bioavailability) with rapid and efficient brain penetration, and was well tolerated in CNS behavioral safety screens. In summary, A-960656 has properties well suited to probe the pharmacology of histamine H(3) receptors in pain. Its potency and efficacy in animal pain models provide support to the notion that histamine H(3) receptor antagonists are effective in attenuating nociceptive processes.


Assuntos
Benzotiazóis/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Neuralgia/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Piridazinas/farmacologia , Receptores Histamínicos H3/metabolismo , Animais , Benzotiazóis/efeitos adversos , Benzotiazóis/metabolismo , Benzotiazóis/farmacocinética , Permeabilidade da Membrana Celular , Inibidores das Enzimas do Citocromo P-450 , Modelos Animais de Doenças , Cães , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Células HEK293 , Coração/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/efeitos adversos , Antagonistas dos Receptores Histamínicos H3/metabolismo , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Osteoartrite do Joelho/tratamento farmacológico , Piridazinas/efeitos adversos , Piridazinas/metabolismo , Piridazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Especificidade por Substrato
2.
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
3.
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
4.
Curr Drug Saf ; 6(5): 277-84, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22424534

RESUMO

A-955840, a selective CB2 agonist, has been shown to elicit concentration-dependent decreases in cardiac contractility in the anesthetized dog (decreased maximal velocity of left ventricular pressure development [LV dP/dt max]). However, it is unknown whether this represents a direct effect or a response dependent on other factors (such as autonomic tone and neurohumoral factors) present in vivo. This study examined if A-955840 had a direct effect on contractility of isolated cardiac myocytes, and if so to determine the potential mechanisms. Contractility was assessed in vitro using percent changes in maximal shortening velocity of sarcomeres (dL/dt max) and fractional shortening of sarcomere length (FS) in rabbit left ventricular myocytes. L-type calcium current in myocytes was recorded using wholecell voltage-clamp techniques. A-955840 reduced dL/dt max and FS in a reversible and concentration-dependent manner with an IC50 of 11.4 µg/mL (based on dL/dt max) which is similar to the estimated IC50 value of 9.8 µg/mL based on the effects of A-955840 on LV dP/dt max in anesthetized dogs. A-955840 (4.1 µg/mL) reduced myocyte contractility (%FS) to a similar extent in the absence and presence of a CB2 antagonist, SR-2 (24.0 ± 3.4 vs 23.1 ± 3.0 %, n=5) or a CB1 antagonist, Rimonabant (18.8 ± 2.3 vs 19.8 ± 2.7 %, n=5). A-955840 (4.1 µg/mL) also reduced L-type calcium current of rabbit ventricular myocytes (1.05 ± 0.11 vs 0.70 ± 0.12 nA, n=5, P < 0.01). These results suggest that A-955840 exerts direct negative inotropic effects on isolated rabbit ventricular myocytes, which is mediated by neither CB2 nor CB1 receptors, and consistent with off-target negative inotropy mediated by inhibition of the cardiac L-type calcium current.


Assuntos
Benzamidas/farmacologia , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Receptor CB2 de Canabinoide/agonistas , Tiazóis/farmacologia , Animais , Benzamidas/administração & dosagem , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Cães , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Concentração Inibidora 50 , Masculino , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Piperidinas/farmacologia , Pirazóis/farmacologia , Coelhos , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto , Sarcômeros/metabolismo , Tiazóis/administração & dosagem
5.
Biochem Pharmacol ; 80(7): 1000-6, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20599796

RESUMO

N'1-(3,3,6,8-tetramethyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yliden)-2-cyanoethanohydrazide (TTYC) increases secretion of glucagon-like peptide-1 and intracellular Ca(2+) concentration in GLUTag cells. The purpose of the present study was to examine if TTYC exerts positive inotropic effects on isolated rabbit ventricular myocytes and in vivo heart in anesthetized rats, and if so to further define the potential mechanism of action. Contractility was assessed in vitro using changes in fractional shortening (FS) of myocyte sarcomere length and in vivo using changes in the velocity of left ventricular pressure. Changes in L-type Ca(2+) current of ventricular myocytes were evaluated using whole-cell voltage-clamp techniques. TTYC increased FS of myocyte sarcomere length in a concentration-dependent manner. The positive inotropic effect was not abrogated by beta-adrenergic blockade (propranolol) or protein kinase A inhibition. TTYC enhanced peak L-type Ca(2+) current in a voltage-dependent manner (current amplitudes increased by 4.0-fold at -10 mV and 1.5-fold at +10 mV). Voltage-dependence of steady-state activation of L-type Ca(2+) current was shifted by 15 mV in the negative direction. Inactivation time course of the L-type Ca(2+) currents at voltages of -10 to 20 mV was significantly slowed by 0.3 microM TTYC. In vivo studies demonstrated that TTYC increased cardiac contractility in a dose-dependent manner. In conclusion, TTYC is a novel L-type Ca(2+) current activator with positive cardiac inotropic effects. Negative shifting of the voltage-dependence of L-type Ca(2+) current activation and reduced inactivation are two mechanisms responsible for the enhanced L-type Ca(2+) current that contribute to the positive inotropic effects.


Assuntos
Cálcio/metabolismo , Contração Miocárdica/efeitos dos fármacos , Animais , Cálcio/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Coração/efeitos dos fármacos , Masculino , Células Musculares/metabolismo , Contração Miocárdica/fisiologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Coelhos , Ratos , Ratos Sprague-Dawley
6.
Bioorg Med Chem Lett ; 20(11): 3295-300, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20457525

RESUMO

A series of quinoline containing histamine H(3) antagonists is reported herein. These analogs were synthesized via the Friedlander quinoline synthesis between an aminoaldehyde intermediate and a methyl ketone allowing for a wide diversity of substituents at the 2-position of the quinoline ring.


Assuntos
Antagonistas dos Receptores Histamínicos H3/farmacologia , Quinolinas/farmacologia , Animais , Humanos , Técnicas In Vitro , Ratos
7.
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
8.
J Med Chem ; 51(5): 1231-41, 2008 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-18260617

RESUMO

A series of benzoisoxazoles and benzoisothiazoles have been synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). Structure-activity relationship studies led to the identification of 3-amino benzo[ d]isoxazoles, incorporating a N, N'-diphenyl urea moiety at the 4-position that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor families of RTKs. Within this series, orally bioavailable compounds possessing promising pharmacokinetic profiles were identified, and a number of compounds demonstrated in vivo efficacy in models of VEGF-stimulated vascular permeability and tumor growth. In particular, compound 50 exhibited an ED 50 of 2.0 mg/kg in the VEGF-stimulated uterine edema model and 81% inhibition in the human fibrosarcoma (HT1080) tumor growth model when given orally at a dose of 10 mg/kg/day.


Assuntos
Isoxazóis/síntese química , Modelos Moleculares , Oxazóis/síntese química , Compostos de Fenilureia/síntese química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacocinética , Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Permeabilidade Capilar/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Edema/tratamento farmacológico , Feminino , Humanos , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Oxazóis/farmacocinética , Oxazóis/farmacologia , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/farmacologia , Fosforilação , Relação Estrutura-Atividade , Útero/irrigação sanguínea , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Med Chem ; 51(3): 380-3, 2008 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-18183944

RESUMO

A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.


Assuntos
Fármacos Antiobesidade/síntese química , Cicloeptanos/síntese química , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Hipolipemiantes/síntese química , Cetoácidos/síntese química , Ureia/análogos & derivados , Ureia/síntese química , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacocinética , Compostos de Bifenilo/farmacologia , Cicloeptanos/farmacocinética , Cicloeptanos/farmacologia , Diacilglicerol O-Aciltransferase/genética , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Cetoácidos/farmacocinética , Cetoácidos/farmacologia , Fígado/metabolismo , Camundongos , Camundongos Mutantes , Estereoisomerismo , Relação Estrutura-Atividade , Triglicerídeos/metabolismo , Ureia/farmacocinética , Ureia/farmacologia , Redução de Peso
10.
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
11.
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
12.
Biochem Pharmacol ; 73(8): 1243-55, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17371699

RESUMO

Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H(3) receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H(3) receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H(3) receptors (H(3), K(i)=1.5 nM) versus off-target receptors and channels (including the hERG K(+) channel, K(i)>9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4)=2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP(450) inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9h, 1.7h in dog, 1.8h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.


Assuntos
Comportamento Animal/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Receptores Histamínicos H3/fisiologia , Animais , Comportamento Animal/fisiologia , Benzofuranos/química , Benzofuranos/farmacologia , Cães , Haplorrinos , Antagonistas dos Receptores Histamínicos/sangue , Humanos , Ratos , Receptores Histamínicos H3/efeitos dos fármacos
13.
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
14.
Bioorg Med Chem Lett ; 17(4): 884-9, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17188866

RESUMO

The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.


Assuntos
Cromonas/síntese química , Cromonas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Depressores do Apetite/farmacologia , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Dieta , Gorduras na Dieta , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Fenfluramina/farmacologia , Indicadores e Reagentes , Camundongos , Conformação Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Relação Estrutura-Atividade
15.
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
16.
J Pharmacol Toxicol Methods ; 50(3): 187-99, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15519905

RESUMO

INTRODUCTION: The human ether-a-go-go-related gene (hERG) encodes a potassium channel responsible for the cardiac delayed rectifier current (IKr) involved in ventricular repolarization. Drugs that block hERG have been associated with QT interval prolongation and serious, sometimes fatal, cardiac arrhythmias (including torsade de pointes). While displacement of [3H]dofetilide, a potent methanesulfonanilide hERG blocker, from cells heterologously expressing hERG has been suggested as a screening assay, questions have been raised about its predictive value. METHODS: To validate the utility of this assay as a screening tool, we performed a series of saturation and competition binding studies using [3H]dofetilide as ligand and either intact cells or membrane preparations from HEK 293 cells stably transfected with hERG K+ channels. The object of these experiments was to (1) compare binding Ki values for 22 hERG blockers using intact cells or membrane homogenates to determine whether maintaining cell integrity enhanced assay reliability; (2) evaluate the ability of different K+ concentrations (2, 5, 10, 20, and 60 mM) to modulate hERG binding; and (3) to establish the predictive value of the assay by comparing Ki values from binding studies at 5 and 60 mM [K+]o to functional IC50 values for hERG current block using 56 structurally diverse drugs. RESULTS: We found (a) comparable Ki values in the intact cell and isolated membrane binding assays, although there were some differences in rank order; (b) increasing [K+]o lowered the Kd and increased the Bmax for [3H]dofetilide, particularly in the membrane assay; and (c) good correlation between binding Ki values and functional IC50 values for hERG current block. DISCUSSION: In conclusion, increasing K+ concentrations results in an increase in both [3H]dofetilide affinity for hERG and available binding sites, particularly when using membrane homogenates. There are no meaningful differences between Ki values when comparing intact cell versus membrane assay, neither are there meaningful trends with increasing [K+]o within assays. There is good correlation between binding Ki values and functional (whole-cell patch clamp) IC50 values at both 5 and 60 mM K+ concentrations (R2 values of .824 and .863, respectively). The simplicity, predictability, and adaptability to high-throughput platforms make the [3H]dofetilide membrane binding assay a useful tool for screening and ranking compounds for their potential to block the hERG K+ channel.


Assuntos
Arritmias Cardíacas , Rim/metabolismo , Fenetilaminas/farmacocinética , Bloqueadores dos Canais de Potássio/farmacocinética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Sulfonamidas/farmacocinética , Antiarrítmicos/farmacologia , Sítios de Ligação , Bioensaio , Linhagem Celular , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go , Humanos , Rim/efeitos dos fármacos , Técnicas de Patch-Clamp , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Trítio
17.
J Med Chem ; 47(5): 1085-97, 2004 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-14971889

RESUMO

The design and synthesis of a series of 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A that are novel, nonpeptide LHRH antagonists, is described. The macrolide antagonist 1, discovered during a screen of our chemical repository, was compared to a macrocyclic peptide antagonist 2 using molecular modeling, thus providing a model for the design of more potent antagonists. Medicinal chemistry efforts to find a replacement for cladinose at position 3 of the erythronolide core provided a series of oxazolidinone carbamates that were equally as active as the cladinose-containing parent macrolides. The descladinose LHRH antagonist 14 has 1-2 nM affinity for both rat and human LHRH receptors and is a potent inhibitor of LH release (pA2 = 8.76) in vitro. In vivo, 14 was found to produce a dose-dependent suppression of LH in male castrate rats via both i.v. and p.o. dosing.


Assuntos
Eritromicina/análogos & derivados , Eritromicina/síntese química , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hexoses/síntese química , Administração Oral , Animais , Células Cultivadas , Cricetinae , Desenho de Fármacos , Eritromicina/farmacologia , Hormônio Liberador de Gonadotropina/sangue , Hormônio Liberador de Gonadotropina/metabolismo , Hexoses/farmacologia , Humanos , Injeções Intravenosas , Masculino , Modelos Moleculares , Orquiectomia , Hipófise/citologia , Hipófise/metabolismo , Ratos , Relação Estrutura-Atividade
18.
Eur J Pharmacol ; 435(1): 79-83, 2002 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-11790381

RESUMO

Bimoclomol has been shown to increase an inducible member of the heat shock protein 70 family (HSP70) and cytoprotect in vitro. Here, we addressed whether oral pretreatment of rats with bimoclomol could elevate myocardial HSP70 and reduce infarct size in a rat model of ischemia and reperfusion. Rats were pretreated with bimoclomol at 3, 6 or 18 h or with 42 degrees thermal stress 24 h before ischemia. Infarct size was significantly decreased 6 h after oral administration of bimoclomol and 24 h after thermal stress. Left ventricles from a separate group of rats were examined for HSP70 levels. Western blots showed a significant increase in HSP70 6 h after oral administration of bimoclomol and 24 h after thermal stress. There was a significant correlation (P<0.05) between HSP70 induction and infarct size reduction, whether produced by thermal stress or oral administration of bimoclomol. Thus, bimoclomol can increase HSP70 and reduce infarct size in a rat model of ischemia and reperfusion.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Imidas/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Miocárdio/metabolismo , Substâncias Protetoras/uso terapêutico , Piridinas/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Infarto do Miocárdio/fisiopatologia , Ratos
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