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1.
Clin Drug Investig ; 33(5): 365-74, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23549864

RESUMO

BACKGROUND: As compared with individual tablets, saxagliptin/metformin immediate release (IR) fixed-dose combination (FDC) tablets offer the potential for increased convenience, compliance, and adherence for patients requiring combination therapy. OBJECTIVES: Two bioequivalence studies assessed the fed-state and the fasted-state bioequivalence of saxagliptin/metformin IR 2.5 mg/500 mg FDC (study 1) and saxagliptin/metformin IR 2.5 mg/1,000 mg FDC (study 2) relative to the same dosage strengths of the individual component tablets [saxagliptin (Onglyza™) and metformin IR (Glucophage(®))] administered concurrently. STUDY DESIGNS: These were randomized, open-label, single-dose, four-period, four-treatment, crossover studies in healthy subjects (n = 24 in each study). The treatments in study 1 were a saxagliptin/metformin IR 2.5 mg/500 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 2.5 mg and metformin IR 500 mg tablets co-administered in the fed state and fasted states on separate occasions. The treatments in study 2 were a saxagliptin/metformin IR 2.5 mg/1,000 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 2.5 mg and metformin IR 1,000 mg co-administered in the fed state and fasted states on separate occasions. The pharmacokinetics, safety, and tolerability of each treatment were evaluated. RESULTS: For both studies, saxagliptin and metformin in the FDCs were bioequivalent to the individual components in both the fed and the fasted states as the limits of the 90 % confidence interval of the ratio of adjusted geometric means for all key pharmacokinetic parameters were contained within the predefined 0.800 to 1.250 bioequivalence criteria. Co-administration of saxagliptin and metformin IR was generally safe and well tolerated as the FDCs or as individual tablets. CONCLUSIONS: Saxagliptin/metformin IR 2.5 mg/500 mg and saxagliptin/metformin IR 2.5 mg/1,000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin of the same strengths in both the fed and the fasted states. No unexpected safety findings were observed with saxagliptin/metformin IR administration. The tolerability of the FDC of saxagliptin/metformin IR was comparable to that of the co-administered individual components. These results indicate that the safety and efficacy profile of co-administration of saxagliptin and metformin can be extended to the saxagliptin/metformin IR FDC tablets.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Adamantano/administração & dosagem , Adamantano/sangue , Adamantano/farmacocinética , Administração Oral , Adulto , Química Farmacêutica , Estudos Cross-Over , Preparações de Ação Retardada , Dipeptídeos/administração & dosagem , Dipeptídeos/sangue , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/sangue , Combinação de Medicamentos , Quimioterapia Combinada , Jejum/sangue , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Masculino , Metformina/administração & dosagem , Metformina/sangue , New Jersey , Período Pós-Prandial , Comprimidos , Equivalência Terapêutica , Adulto Jovem
2.
Clin Pharmacokinet ; 50(4): 253-65, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21348538

RESUMO

BACKGROUND AND OBJECTIVE: Patients with type 2 diabetes mellitus often have impaired renal function or may have impaired hepatic function, which can pose significant safety and tolerability issues for antihyperglycaemic pharmacotherapies. Therefore, the pharmacokinetics and tolerability of saxagliptin and its pharmacologically active metabolite, 5-hydroxy saxagliptin, in nondiabetic subjects with mild, moderate or severe renal or hepatic impairment, or end-stage renal disease (ESRD) were compared with saxagliptin and metabolite pharmacokinetics and tolerability in healthy adult subjects. METHODS: Two open-label, parallel-group, single-dose studies were conducted. Subjects received a single oral dose of saxagliptin 10 mg (Onglyza™). RESULTS: Compared with healthy subjects, the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) for saxagliptin was 16%, 41% and 108% (2.1-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. AUC∞ values for 5-hydroxy saxagliptin were 67%, 192% (2.9-fold) and 347% (4.5-fold) higher in subjects with mild, moderate or severe renal impairment, respectively. As creatinine clearance (CLCR) values decreased, saxagliptin and 5-hydroxy saxagliptin AUC∞ generally increased or became more variable. Twenty-three percent of the saxagliptin dose (measured as the sum of saxagliptin and 5-hydroxy saxagliptin) was cleared by haemodialysis in a 4-hour dialysis session. In the hepatic impairment study, the differences in exposure to saxagliptin and 5-hydroxy saxagliptin were less than 2-fold across all groups. As compared with healthy subjects matched for age, bodyweight, sex and smoking status, the AUC∞ values for saxagliptin were 10%, 38% and 77% higher in subjects with mild, moderate or severe hepatic impairment, respectively. These values were 22%, 7% and 33% lower, respectively, for 5-hydroxy saxagliptin compared with matched healthy subjects. CONCLUSIONS: One-half the usual dose of saxagliptin 5 mg (i.e. 2.5 mg orally once daily) is recommended for patients with moderate (CLCR 30-50 mL/min) or severe (CLCR<30 mL/min not on dialysis) renal impairment or ESRD, but no dose adjustment is recommended for those with mild renal impairment or any degree of hepatic impairment.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Insuficiência Hepática/metabolismo , Hipoglicemiantes/farmacocinética , Insuficiência Renal/metabolismo , Adamantano/efeitos adversos , Adamantano/análise , Adamantano/sangue , Adamantano/farmacocinética , Adamantano/urina , Adulto , Idoso , Diabetes Mellitus Tipo 2/tratamento farmacológico , Soluções para Diálise/química , Dipeptídeos/efeitos adversos , Dipeptídeos/análise , Dipeptídeos/sangue , Dipeptídeos/urina , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/análise , Feminino , Meia-Vida , Insuficiência Hepática/sangue , Insuficiência Hepática/urina , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/análise , Falência Renal Crônica/sangue , Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Diálise Renal , Insuficiência Renal/sangue , Insuficiência Renal/urina , Índice de Gravidade de Doença
3.
Bioorg Med Chem Lett ; 17(12): 3254-7, 2007 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-17451949

RESUMO

AMP-activated protein kinase (AMPK) is well established as a sensor and regulator of intracellular and whole-body energy metabolism. A high-throughput screen was performed in order to identify chemotypes that are bound by AMPK. A novel thienopyridone compound (1) was identified and subsequently optimized. The structure-activity relationships that emerged from this effort are described.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Complexos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Piridinas/farmacologia , Proteínas Quinases Ativadas por AMP , Bioensaio , Metabolismo Energético/fisiologia , Ativação Enzimática/fisiologia , Ativadores de Enzimas/química , Piridinas/química , Relação Estrutura-Atividade
4.
J Med Chem ; 50(1): 149-64, 2007 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-17201418

RESUMO

Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/síntese química , Piperazinas/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/genética , Adamantano/farmacocinética , Animais , Linhagem Celular , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Piperazinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição Tecidual
5.
Bioorg Med Chem Lett ; 17(6): 1803-7, 2007 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-17234407

RESUMO

The structure-activity relationship study focused on the polar region of the HTS hit A-80040 (1) producing several series of potent and selective ACC2 inhibitors. The SAR suggests a compact lipophilic pocket that does not tolerate polar and ionic groups. Replacement of the hydroxyurea group with isoxazoles improves ACC2 selectivity while maintaining potency. Variations at the propargylic site of 11a reduce ACC2 potency.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Alcinos/síntese química , Alcinos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Acetil-CoA Carboxilase/genética , Fenômenos Químicos , Físico-Química , Humanos , Hidroxiureia/química , Isoxazóis/síntese química , Isoxazóis/farmacologia , Conformação Molecular , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 16(23): 5958-62, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16996734

RESUMO

A series of potent and selective adamantane aminoamide 11-beta-HSD-1 inhibitors has been optimized. Chemically these studies were expedited by utilizing readily obtained amino acids as starting materials or an isocyanide multicomponent reaction. Structure-activity relationship studies resulted in the discovery of dual human and mouse 11-beta-HSD-1 potent and selective inhibitors like adamantane 11 and related compounds with high metabolic stability and robust pharmacokinetic profiles.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/síntese química , Adamantano/farmacologia , Cianetos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Adamantano/química , Adamantano/farmacocinética , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 16(23): 6078-81, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16973360

RESUMO

Structure-activity relationships for a recently discovered thiazolyl phenyl ether series of acetyl-CoA carboxylase (ACC) inhibitors were investigated. Preliminary efforts to optimize the series through modification of the distal aryl ether moiety of the lead scaffold resulted in the identification of compounds exhibiting low-nanomolar potency and isozyme-selective ACC2 activity.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Inibidores Enzimáticos/química , Estrutura Molecular , Éteres Fenílicos/síntese química , Relação Estrutura-Atividade
10.
J Med Chem ; 49(13): 3770-3, 2006 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-16789734

RESUMO

A structurally novel acetyl-CoA carboxylase (ACC) inhibitor is identified from high-throughput screening. A preliminary structure-activity relationship study led to the discovery of potent dual ACC1/ACC2 and ACC2 selective inhibitors against human recombinant ACC1 and ACC2. Selective ACC2 inhibitors exhibited IC50<20 nM and >1000-fold selectivity against ACC1. (S)-Enantiomer 9p exhibited high ACC2 activity and lowered muscle malonyl-CoA dose-dependently in acute rodent studies, whereas (R)-enantiomer 9o was weak and had no effect on the malonyl-CoA level.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Alcinos/síntese química , Hipoglicemiantes/síntese química , Tiazóis/síntese química , Acetil-CoA Carboxilase/genética , Alcinos/farmacocinética , Alcinos/farmacologia , Animais , Linhagem Celular , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Malonil Coenzima A/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia
11.
Cell Metab ; 3(6): 403-16, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16753576

RESUMO

AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole-body energy metabolism. We have identified a thienopyridone family of AMPK activators. A-769662 directly stimulated partially purified rat liver AMPK (EC50 = 0.8 microM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC50 = 3.2 microM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl CoA levels and the respiratory exchange ratio, VCO2/VO2, indicating an increased rate of whole-body fatty acid oxidation. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK, G6Pase, and FAS, lowered plasma glucose by 40%, reduced body weight gain and significantly decreased both plasma and liver triglyceride levels. These results demonstrate that small molecule-mediated activation of AMPK in vivo is feasible and represents a promising approach for the treatment of type 2 diabetes and the metabolic syndrome.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/química , Ativadores de Enzimas/uso terapêutico , Síndrome Metabólica/tratamento farmacológico , Complexos Multienzimáticos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Pironas/química , Pironas/uso terapêutico , Tiofenos/química , Tiofenos/uso terapêutico , Proteínas Quinases Ativadas por AMP , Animais , Compostos de Bifenilo , Linhagem Celular , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Ativadores de Enzimas/farmacologia , Ácido Graxo Sintases/efeitos dos fármacos , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Glucose-6-Fosfatase/efeitos dos fármacos , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Síndrome Metabólica/metabolismo , Metformina/química , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Camundongos Obesos , Peso Molecular , Complexos Multienzimáticos/efeitos dos fármacos , Fosfoenolpiruvato Carboxiquinase (GTP)/efeitos dos fármacos , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Pironas/farmacologia , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Tiofenos/farmacologia
12.
Assay Drug Dev Technol ; 2(1): 63-9, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15090211

RESUMO

The modulation of fatty acid metabolism and especially the stimulation of fatty acid oxidation in liver or skeletal muscle are attractive therapeutic approaches for the treatment of obesity and the associated insulin resistance. However, current beta-oxidation assays are run in very low throughput, which represents an obstacle for drug discovery in this area. Here we describe results for a 48-well beta-oxidation assay using a new instrument design. A connecting chamber links two adjacent wells to form an experimental unit, in which one well contains the beta-oxidation reaction and the other captures CO(2). The experimental units are sealed from each other and from the outside to prevent release of radioactivity from the labeled substrate. CO(2) capture in this instrument is linear with time and over the relevant experimental range of substrate concentration. Cellular viability is maintained in the sealed environment, and cells show the expected responses to modulators of beta-oxidation, such as the AMP kinase activator 5-aminoimidazole carboxamide riboside. Data are presented for different lipid substrates and cell lines. The increased throughput of this procedure compared with previously described methods should facilitate the evaluation of compounds that modulate fatty acid metabolism.


Assuntos
Bioensaio/instrumentação , Ácidos Graxos/metabolismo , Animais , Caprilatos/metabolismo , Dióxido de Carbono/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Separação Celular , Sobrevivência Celular/efeitos dos fármacos , Glucose/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Técnicas In Vitro , Neoplasias Hepáticas/metabolismo , Oxirredução , Palmitatos/metabolismo , Ratos , Ratos Sprague-Dawley
13.
J Biomol Screen ; 9(2): 112-21, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15006134

RESUMO

A novel and innovative high-throughput screening assay was developed to identify both activators and inhibitors of AMP-activated protein kinase (AMPK) using microarrayed compound screening (microARCS) technology. Test compounds were arrayed at a density of 8640 on a polystyrene sheet, and the enzyme and peptide substrate were introduced into the assay by incorporating them into an agarose gel followed by placement of the gels onto the compound sheet. Adenosine triphosphate (ATP) was delivered via a membrane, and the phosphorylated biotinylated substrate was captured onto a streptavidin affinity membrane (SAM trade mark ). For detection, the SAM trade mark was removed, washed, and imaged on a phosphor screen overnight. A library of more than 700,000 compounds was screened using this format to identify novel activators and inhibitors of AMPK.


Assuntos
Complexos Multienzimáticos/antagonistas & inibidores , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP , Trifosfato de Adenosina/análise , Animais , Miniaturização , Complexos Multienzimáticos/análise , Proteínas Serina-Treonina Quinases/análise , Ratos , Sensibilidade e Especificidade , Fatores de Tempo
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