Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 51
Filtrar
1.
J Pharmacol Exp Ther ; 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849142

RESUMO

Acute Kidney Injury (AKI) is characterized by an abrupt decline in kidney function and has been associated with excess risks of death, kidney disease progression, and cardiovascular events. The kidney has a high energetic demand with mitochondrial health being essential to renal function and damaged mitochondria has been reported across AKI subtypes. 5' adenosine monophosphate-activated protein kinase (AMPK) activation preserves cellular energetics through improvement of mitochondrial function and biogenesis when ATP levels are low such as under ischemia-induced AKI. We developed a selective potent small molecule pan AMPK activator, compound 1, and tested its ability to increase AMPK activity and preserve kidney function during ischemia/reperfusion injury in rats. A single administration of 1 caused sustained activation of AMPK for at least 24 hours, protected against acute tubular necrosis, and reduced clinical markers of tubular injury such as NephroCheck and Fractional Excretion of Sodium (FENa). Reduction in plasma creatinine and increased Glomerular Filtration Rate (GFR) indicated preservation of kidney function. Surprisingly, we observed a strong diuretic effect of AMPK activation associated with natriuresis both with and without AKI. Our findings demonstrate that activation of AMPK leads to protection of tubular function under hypoxic/ischemic conditions which holds promise as a potential novel therapeutic approach for AKI. Significance Statement No approved pharmacological therapies currently exist for acute kidney injury. We developed Compound 1 which dose-dependently activated AMPK in the kidney and protected kidney function and tubules after ischemic renal injury in the rat. This was accompanied by natriuresis in injured as well as uninjured rats.

2.
ACS Med Chem Lett ; 10(1): 16-21, 2019 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-30655940

RESUMO

GPR40 is a G-protein-coupled receptor which mediates fatty acid-induced glucose-stimulated insulin secretion from pancreatic beta cells and incretion release from enteroendocrine cells of the small intestine. GPR40 full agonists exhibit superior glucose lowering compared to partial agonists in preclinical species due to increased insulin and GLP-1 secretion, with the added benefit of promoting weight loss. In our search for potent GPR40 full agonists, we discovered a superagonist which displayed excellent in vitro potency and superior efficacy in the Gαs-mediated signaling pathway. Most synthetic GPR40 agonists have a carboxylic acid headgroup, which may cause idiosyncratic toxicities, including drug-induced-liver-injury (DILI). With a methyl group and a fluorine atom substituted at the α-C of the carboxylic acid group, 19 is not only highly efficacious in lowering glucose and body weight in rodent models but also has a low DILI risk due to its stable acylglucuronide metabolite.

3.
Mol Pharmacol ; 93(6): 581-591, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29572336

RESUMO

GPR40 is a clinically validated molecular target for the treatment of diabetes. Many GPR40 agonists have been identified to date, with the partial agonist fasiglifam (TAK-875) reaching phase III clinical trials before its development was terminated due to off-target liver toxicity. Since then, attention has shifted toward the development of full agonists that exhibit superior efficacy in preclinical models. Full agonists bind to a distinct binding site, suggesting conformational plasticity and a potential for biased agonism. Indeed, it has been suggested that alternative pharmacology may be required for meaningful efficacy. In this study, we described the discovery and characterization of Compound A, a newly identified GPR40 allosteric full agonist highly efficacious in human islets at potentiating glucose-stimulated insulin secretion. We compared Compound A-induced GPR40 activity to that induced by both fasiglifam and AM-1638, another allosteric full agonist previously reported to be highly efficacious in preclinical models, at a panel of G proteins. Compound A was a full agonist at both the Gαq and Gαi2 pathways, and in contrast to fasiglifam Compound A also induced Gα12 coupling. Compound A and AM-1638 displayed similar activity at all pathways tested. The Gα12/Gα13-mediated signaling pathway has been linked to protein kinase D activation as well as actin remodeling, well known to contribute to the release of insulin vesicles. Our data suggest that the pharmacology of GPR40 is complex and that Gα12/Gα13-mediated signaling, which may contribute to GPR40 agonists therapeutic efficacy, is a specific property of GPR40 allosteric full agonists.


Assuntos
Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Glucose/metabolismo , Secreção de Insulina/fisiologia , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Benzofuranos/farmacologia , Células CHO , Linhagem Celular , Cricetulus , Células HEK293 , Humanos , Hipoglicemiantes/farmacologia , Secreção de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Proteína Quinase C/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Sulfonas/farmacologia
4.
Bioorg Med Chem Lett ; 28(4): 720-726, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29366647

RESUMO

Compound 12 is a GPR40 agonist that realizes the full magnitude of efficacy possible via GPR40 receptor agonism. In vitro and in vivo studies demonstrated superior glucose lowering by 12 compared to fasiglifam (TAK-875), in a glucose dependent manner. The enhanced efficacy observed with the full agonist 12 was associated with both direct and indirect stimulation of insulin secretion.


Assuntos
Hipoglicemiantes/farmacologia , Pirazinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Benzofuranos/farmacologia , Compostos de Bifenilo/farmacologia , Células CHO , Cricetulus , Cães , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Glucuronídeos/biossíntese , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Macaca fascicularis , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Fenilpropionatos/farmacologia , Piperidinas/farmacologia , Pirazinas/síntese química , Pirazinas/química , Pirazinas/metabolismo , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacologia
5.
Toxicol Sci ; 163(2): 374-384, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28206647

RESUMO

TAK-875, a GPR40 agonist, was withdrawn from Phase III clinical trials due to drug-induced liver injury (DILI). Mechanistic studies were conducted to identify potential DILI hazards (covalent binding burden (CVB), hepatic transporter inhibition, mitochondrial toxicity, and liver toxicity in rats) associated with TAK-875. Treatment of hepatocytes with radiolabeled TAK-875 resulted in a CVB of 2.0 mg/day, which is above the threshold of 1 mg/day considered to be a risk for DILI. Covalent binding to hepatocytes was due to formation of a reactive acyl glucuronide (AG) and, possibly, an acyl-CoA thioester intermediate. Formation of TAK-875AG in hepatocytes and/or in vivo was in the order of non-rodents > human (in vitro only) > rat. These data suggest that non-rodents, and presumably humans, form TAK-875AG more efficiently than rats, and that AG-mediated toxicities in rats may only occur at high doses. TAK-875 (1000 mg/kg/day) formed significant amounts of AG metabolite (≤32.7 µM) in rat liver that was associated with increases in ALT (×4), bilirubin (×9), and bile acids (×3.4), and microscopic findings of hepatocellular hypertrophy and single cell necrosis. TAK-875 and TAK-875AG had similar potencies (within 3-fold) for human multi-drug resistant associated protein 2/4 (MRP2/4) and bile salt export pump, but TAK-875AG was exceptionally potent against MRP3 (0.21 µM). Inhibition of MRPs may contribute to liver accumulation of TAK-875AG. TAK-875 also inhibited mitochondrial respiration in HepG2 cells, and mitochondrial Complex 1 and 2 activities in isolated rat mitochondria. In summary, formation of TAK-875AG, and possibly TAK-875CoA in hepatocytes, coupled with inhibition of hepatic transporters and mitochondrial respiration may be key contributors to TAK-875-mediated DILI.


Assuntos
Benzofuranos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatócitos/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Sulfonas/toxicidade , Animais , Benzofuranos/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cães , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Macaca fascicularis , Mitocôndrias Hepáticas/fisiologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Transportadores de Ânions Orgânicos/genética , Consumo de Oxigênio/efeitos dos fármacos , Ligação Proteica , Ratos , Especificidade da Espécie , Sulfonas/metabolismo
6.
Bioorg Med Chem Lett ; 28(3): 429-436, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29258772

RESUMO

GPR40 partial agonism is a promising new mechanism for the treatment of type 2 diabetes mellitus with clinical proof of concept. Most of the GPR40 agonists in the literature have a carboxylic acid functional group, which may pose a risk for idiosyncratic drug toxicity. A novel series of GPR40 agonists containing a tetrazole as a carboxylic acid bioisostere was identified. This series of compounds features a benzo[b]thiophene as the center ring, which is prone to oxidation during phase 1 metabolism. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for in vivo evaluation. The compounds are efficacious at lowering blood glucose in a SD rat oGTT model.


Assuntos
Descoberta de Drogas , Receptores Acoplados a Proteínas G/agonistas , Tetrazóis/farmacologia , Tiofenos/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química , Tiofenos/química
7.
Eur J Med Chem ; 138: 830-853, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28735214

RESUMO

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC50s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg). A multi-parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Indazóis/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Indazóis/administração & dosagem , Indazóis/química , Ligantes , Masculino , Camundongos , Camundongos Obesos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Relação Estrutura-Atividade , Receptor ERRalfa Relacionado ao Estrogênio
9.
J Med Chem ; 58(9): 3859-74, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25850459

RESUMO

Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 4 antagonized capsaicin-induced Ca(2+) influx, with an IC50 value of 4.6 nM. In the complete Freund's adjuvant- and carrageenan-induced thermal hypersensitivity models, 4 exhibited full efficacy, with ED80 values of 7.8 and 0.5 mg/kg, respectively, corresponding to plasma levels of 270.8 and 9.2 ng/mL, respectively. On the basis of its superior pharmacologic and safety profile, 4 (mavatrep) was selected for clinical development for the treatment of pain.


Assuntos
Analgésicos/química , Benzimidazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Carragenina , Cães , Adjuvante de Freund , Células HEK293 , Haplorrinos , Temperatura Alta , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/fisiopatologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
10.
Crit Care Med ; 42(5): e355-63, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24595220

RESUMO

OBJECTIVES: Mild decrease in core temperature (therapeutic hypothermia) provides lasting neuroprotection following cardiac arrest or cerebral ischemia. However, current methods for producing therapeutic hypothermia trigger a cold-defense response that must be countered by sedatives, muscle paralytics, and mechanical ventilation. We aimed to determine methods for producing hypothermia in the conscious mouse by targeting two transient receptor potential channels involved in thermoregulation, two transient receptor potential (TRP) channels involved in thermoregulation, TRP vanilloid 1 (TRPV1) and TRP melastatin 8 (TRPM8). DESIGN: Controlled prospective animal study. SETTING: Research laboratory at academic medical center. SUBJECTS: Conscious unrestrained young and aged male mice. INTERVENTIONS: Mice were treated with the TRPV1 agonist dihydrocapsaicin, a TRPM8 inhibitor ("compound 5"), or their combination and the effects on core temperature (Tcore) were measured by implanted thermocouples and wireless transponders. MEASUREMENTS AND MAIN RESULTS: TRPV1 agonist dihydrocapsaicin produced a dose-dependent (2-4 mg/kg s.c.) drop in Tcore. A loading dose followed by continuous infusion of dihydrocapsaicin produced a rapid and prolonged (> 6 hr) drop of Tcore within the therapeutic range (32-34°C). The hypothermic effect of dihydrocapsaicin was augmented in aged mice and was not desensitized with repeated administration. TRPM8 inhibitor "compound 5" (20 mg/kg s.c.) augmented the drop in core temperature during cold exposure (8°C). When "compound 5" (30 mg/kg) was combined with dihydrocapsaicin (1.25-2.5 mg/kg), the drop in Tcore was amplified and prolonged. CONCLUSIONS: Activating warm receptors (TRPV1) produced rapid and lasting hypothermia in young and old mice. Furthermore, hypothermia induced by TRPV1 agonists was potentiated and prolonged by simultaneous inhibition of TRPM8.


Assuntos
Benzimidazóis/farmacologia , Regulação da Temperatura Corporal/fisiologia , Capsaicina/análogos & derivados , Hipotermia Induzida/métodos , Isoxazóis/farmacologia , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPV/agonistas , Fatores Etários , Análise de Variância , Animais , Capsaicina/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Canais de Cátion TRPM/administração & dosagem , Canais de Cátion TRPV/administração & dosagem
11.
Bioorg Med Chem Lett ; 23(23): 6363-9, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24138939

RESUMO

Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.


Assuntos
Amidas/farmacologia , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Animais , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
12.
Am J Physiol Regul Integr Comp Physiol ; 305(9): R1040-50, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24005250

RESUMO

Mild decrease of core temperature (32-34°C), also known as therapeutic hypothermia, is a highly effective strategy of neuroprotection from ischemia and holds significant promise in the treatment of stroke. However, induction of hypothermia in conscious stroke patients is complicated by cold-defensive responses, such as shivering and tachycardia. Although multiple thermoregulatory responses may be altered by modulators of thermosensitive ion channels, TRPM8 (transient receptor potential melastatin 8) and TRPV1 (TRP vanilloid 1), it is unknown whether these agents affect cold-induced shivering and tachycardia. The current study aimed to determine the effects of TRPM8 inhibition and TRPV1 activation on the shivering and tachycardic responses to external cooling. Conscious mice were treated with TRPM8 inhibitor compound 5 or TRPV1 agonist dihydrocapsaicin (DHC) and exposed to cooling at 10°C. Shivering was measured by electromyography using implanted electrodes in back muscles, tachycardic response by electrocardiography, and core temperature by wireless transmitters in the abdominal cavity. The role of TRPM8 was further determined using TRPM8 KO mice. TRPM8 ablation had no effect on total electromyographic muscle activity (vehicle: 24.0 ± 1.8; compound 5: 23.8 ± 2.0; TRPM8 KO: 19.7 ± 1.9 V·s/min), tachycardia (ΔHR = 124 ± 31; 121 ± 13; 121 ± 31 beats/min) and drop in core temperature (-3.6 ± 0.1; -3.4 ± 0.4; -3.6 ± 0.5°C) during cold exposure. TRPV1 activation substantially suppressed muscle activity (vehicle: 25.6 ± 3.0 vs. DHC: 5.1 ± 2.0 V·s/min), tachycardia (ΔHR = 204 ± 25 vs. 3 ± 35 beats/min) and produced a profound drop in core temperature (-2.2 ± 0.6 vs. -8.9 ± 0.6°C). In conclusion, external cooling-induced shivering and tachycardia are suppressed by TRPV1 activation, but not by TRPM8 inhibition. This suggests that TRPV1 agonists may be combined with external physical cooling to achieve more rapid and effective hypothermia.


Assuntos
Benzimidazóis/farmacologia , Capsaicina/análogos & derivados , Frequência Cardíaca/efeitos dos fármacos , Hipotermia Induzida/efeitos adversos , Estremecimento/efeitos dos fármacos , Canais de Cátion TRPM/antagonistas & inibidores , Canais de Cátion TRPV/agonistas , Taquicardia/prevenção & controle , Animais , Capsaicina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Canais de Cátion TRPM/deficiência , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPV/metabolismo , Taquicardia/etiologia , Taquicardia/genética , Taquicardia/metabolismo , Taquicardia/fisiopatologia , Fatores de Tempo
13.
Bioorg Med Chem Lett ; 22(5): 1903-7, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22330635

RESUMO

Thermosensitive transient receptor potential melastatin 8 (TRPM8) antagonists are considered to be potential therapeutic agents for the treatment of cold hypersensitivity. The discovery of a new class of TRPM8 antagonists that shows in vivo efficacy in the rat chronic constriction injury (CCI)-induced model of neuropathic pain is described.


Assuntos
Analgésicos/química , Analgésicos/uso terapêutico , Benzimidazóis/química , Benzimidazóis/uso terapêutico , Hiperalgesia/tratamento farmacológico , Neuralgia/tratamento farmacológico , Canais de Cátion TRPM/antagonistas & inibidores , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Temperatura Baixa , Cães , Células HEK293 , Humanos , Ratos , Canais de Cátion TRPM/metabolismo
14.
J Med Chem ; 54(22): 7860-83, 2011 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-22039836

RESUMO

A class of potent inhibitors of colony-stimulating factor-1 receptor (CSF-1R or FMS), as exemplified by 8 and 21, was optimized to improve pharmacokinetic and pharmacodynamic properties and potential toxicological liabilities. Early stage absorption, distribution, metabolism, and excretion assays were employed to ensure the incorporation of druglike properties resulting in the selection of several compounds with good activity in a pharmacodynamic screening assay in mice. Further investigation, utilizing the type II collagen-induced arthritis model in mice, culminated in the selection of anti-inflammatory development candidate JNJ-28312141 (23, FMS IC(50) = 0.69 nM, cell assay IC(50) = 2.6 nM). Compound 23 also demonstrated efficacy in rat adjuvant and streptococcal cell wall-induced models of arthritis and has entered phase I clinical trials.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Imidazóis/síntese química , Piperidinas/síntese química , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/etiologia , Artrite Experimental/patologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Feminino , Humanos , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacologia , Conformação Proteica , Ratos , Ratos Endogâmicos Lew , Receptor de Fator Estimulador de Colônias de Macrófagos/química , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade
15.
J Med Chem ; 54(3): 788-808, 2011 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-21218783

RESUMO

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 µM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.


Assuntos
Éteres/síntese química , Hipoglicemiantes/síntese química , Receptores de Estrogênio/metabolismo , Tiazolidinedionas/síntese química , Administração Oral , Animais , Ligação Competitiva , Disponibilidade Biológica , Cristalografia por Raios X , Diabetes Mellitus/tratamento farmacológico , Cães , Éteres/farmacocinética , Éteres/farmacologia , Feminino , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Insulina/sangue , Resistência à Insulina , Ligantes , Macaca fascicularis , Masculino , Camundongos , Camundongos Knockout , Modelos Moleculares , Estrutura Molecular , Obesidade/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptores de Estrogênio/genética , Relação Estrutura-Atividade , Tiazolidinedionas/farmacocinética , Tiazolidinedionas/farmacologia , Triglicerídeos/sangue , Receptor ERRalfa Relacionado ao Estrogênio
16.
Med Res Rev ; 31(2): 202-83, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19967784

RESUMO

Thromboembolic diseases are the leading causes of morbidity and mortality in the developed world. Anticoagulants provide effective treatment for venous or arterial thromboembolism. Two coagulation factors, factor Xa (fXa) and thrombin, are the primary targets under active investigation for anticoagulant therapy. fXa, in contrast to the multifunctional roles of thrombin in the coagulation cascade, converts prothrombin to thrombin collectively at the junction of the intrinsic and extrinsic pathway of coagulation. The effectiveness of fXa inhibitors as antithrombotic agents and their potentially reduced bleeding risks may offer superior therapeutic profiles with respect to thrombin inhibitors. After decades of research, many fXa inhibitors are now in the advanced stages of clinical trials. Unlike most reviews, which only provide incremental updates, this review provides an overview of fXa and the medicinal chemistry of its inhibitors. Overviews on coagulation models, antithrombotic therapy, and fXa will be provided, followed by the evolution of the medicinal chemistry of fXa inhibitors over the past few decades.


Assuntos
Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Inibidores do Fator Xa , Tromboembolia/tratamento farmacológico , Animais , Anticoagulantes/química , Coagulação Sanguínea/efeitos dos fármacos , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Humanos
17.
J Med Chem ; 54(1): 233-47, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-21128593

RESUMO

Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that is thermoresponsive to cool to cold temperatures (8-28 °C) and also may be activated by chemical agonists such as menthol and icilin. Antagonism of TRPM8 activation is currently under investigation for the treatment of painful conditions related to cold, such as cold allodynia and cold hyperalgesia. The design, synthesis, and optimization of a class of selective TRPM8 antagonists based on a benzimidazole scaffold is described, leading to the identification of compounds that exhibited potent antagonism of TRPM8 in cell-based functional assays for human, rat, and canine TRPM8 channels. Numerous compounds in the series demonstrated excellent in vivo activity in the TRPM8-selective "wet-dog shakes" (WDS) pharmacodynamic model and in the rat chronic constriction injury (CCI)-induced model of neuropathic pain. Taken together, the present results suggest that the in vivo antagonism of TRPM8 constitutes a viable new strategy for treating a variety of disorders associated with cold hypersensitivity, including certain types of neuropathic pain.


Assuntos
Analgésicos/síntese química , Benzimidazóis/síntese química , Isoxazóis/síntese química , Canais de Cátion TRPM/antagonistas & inibidores , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Constrição Patológica/tratamento farmacológico , Constrição Patológica/fisiopatologia , Cães , Células HEK293 , Humanos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Técnicas In Vitro , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Macaca fascicularis , Microssomos Hepáticos/metabolismo , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Ratos , Relação Estrutura-Atividade
20.
J Med Chem ; 53(4): 1843-56, 2010 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-20102150

RESUMO

We have identified RWJ-671818 (8) as a novel, low molecular weight, orally active inhibitor of human alpha-thrombin (K(i) = 1.3 nM) that is potentially useful for the acute and chronic treatment of venous and arterial thrombosis. In a rat deep venous thrombosis model used to assess antithrombotic efficacy, oral administration of 8 at 30 and 50 mg/kg reduced thrombus weight by 87 and 94%, respectively. In an anesthetized rat antithrombotic model, where electrical stimulation of the carotid artery created a thrombus, 8 prolonged occlusion time 2- and 3-fold at 0.1 and 1.0 mg/kg, i.v., respectively, and more than doubled activated clotting time and activated partial thromboplastin time at the higher dose. This compound had excellent oral bioavailability of 100% in dogs with an estimated half-life of approximately 3 h. On the basis of its noteworthy preclinical data, 8 was advanced into human clinical trials and successfully progressed through phase 1 studies.


Assuntos
Anticoagulantes/síntese química , Fibrinolíticos/síntese química , Guanidinas/síntese química , Pirazinas/síntese química , Trombina/antagonistas & inibidores , Motivos de Aminoácidos , Animais , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Células CACO-2 , Cristalografia por Raios X , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Cães , Método Duplo-Cego , Eletrocardiografia , Feminino , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacologia , Guanidinas/farmacocinética , Guanidinas/farmacologia , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Pirazinas/farmacocinética , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Relação Estrutura-Atividade , Trombina/química , Trombose Venosa/sangue , Trombose Venosa/tratamento farmacológico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...