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1.
Neurol Res ; 41(11): 1034-1042, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31584350

RESUMO

Objectives: To investigate the thrombolysis with recombinant human prourokinase (rhPro-UK) on thromboembolic stroke in rats at different therapeutic time windows (TTW). Methods: Rats were subjected to embolic middle cerebral artery occlusion. RhPro-UK and positive control drugs rt-PA,UK were administered 3 h, 4.5 h, 6 h after inducing thromboem-bolic stroke. Neurological deficit scoring (NDS) was evaluated at 6 h and 24 h after the treatment. The lesion volume in cerebral hemispheres was measured by MRI scanning machine after 6 h of thrombolysis, and the infarct volume was measured by TTC stain, together with hemorrhagic volume quantified by a spectrophotometric assay after 24 h of thrombolysis. Results: RhPro-UK 10, 20 × 104 U/kg significantly improved the NDS after cerebral thromboembolism in rats at 3 h, 4.5 h TTW, and at the 6 h TTW, the NDS was improved by 28.0% (P = 0.0690) and 29.2% (P = 0.0927) at 6 h and 24 h after rhPro-UK 20 ×104 U/kg administration, respectively. RhPro-UK 10, 20 × 104 U/kg significantly reduced the brain lesions measured by MRI at 3 h and 4.5 h TTW. RhPro-UK 10, 20 × 104 U/kg significantly reduced the cerebral infarction measured by TTC at 3 h, 4.5 h TTW. There was no increase in cerebral hemorrhage compared with untreated group after rhPro-UK administration. Conclusions: RhPro-UK had an obvious therapeutic effect on ischemic stroke caused by thrombosis, and could be started within 4.5 h TTW with less side effects of cerebral hemorrhage than that of UK.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Embolia Intracraniana/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/farmacologia , Animais , Hemorragia Cerebral/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Embolia Intracraniana/complicações , Masculino , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicações , Tromboembolia/complicações , Tromboembolia/tratamento farmacológico , Terapia Trombolítica/métodos , Fatores de Tempo
2.
J Mol Model ; 25(8): 235, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332539

RESUMO

Menthol is an often used skin penetration enhancer because of its high efficiency and relative safety, but the mechanism how it works has not been fully understood up to date. In this study, quercetin was used as a model molecule to investigate the permeability enhancement of menthol through skin lipids. The skin is modeled as a ceramide (CER2) bilayer. Potential of mean force (PMF) calculations on quercetin in both CER2 and menthol-involved CER2 bilayers have been performed. The results show that the free energy minimum of quercetin in the presence of menthol molecules shifts toward the headgroup region of the bilayer, and the central energy barrier decreases, facilitating the penetration of quercetin. The presence of menthol molecules enhances the permeability of quercetin. This study may shed light on the mechanism of penetration enhancer, providing useful information in the design of more efficient transdermal drug delivery system. Graphical abstract Quercetin was used as a model molecule to investigate the permeability enhancement of menthol through skin lipids. Potential of mean force calculations reveal that the central energy barrier of quercetin decreases in the presence of menthol, facilitating the penetration of quercetin. Our results are helpful to understand the mechanism of penetration enhancer, aiding in the design of more efficient transdermal drug delivery system.


Assuntos
Mentol/farmacologia , Simulação de Dinâmica Molecular , Quercetina/farmacologia , Pele/efeitos dos fármacos , Ligação de Hidrogênio , Mentol/química , Permeabilidade , Quercetina/química , Reprodutibilidade dos Testes , Termodinâmica
3.
J Thromb Thrombolysis ; 47(1): 80-86, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30298304

RESUMO

In recent years, oral factor Xa inhibitors have become a research focus as anticoagulant drugs. Zifaxaban is the first oral FXa inhibitor to enter clinical trials in China. The aim of this study was to determine the inhibitory effect of zifaxaban on thrombosisthrough a model ofinferior vena cava (IVC) thrombosis in rabbits. IVC thrombosis model was established by electrical injury and stenosis, and zifaxaban was administered (p.o.) for 5 consecutive days, then coagulation indicators and bleeding were observed. The results showed that zifaxaban had obvious inhibitory effects on FXa, and had a significant inhibitory effect on IVC thrombosis induced by electrical damage and stenosis. The effect of zifaxaban was similar to that of rivaroxaban, but the bleeding side-effects of zifaxaban were less severe than those of rivaroxaban. Zifaxaban could prolong the prothrombin time and activated partial thromboplastin time of plasma similar to that of other oral FXa inhibitors. Zifaxaban had a significant inhibitory effect on FXa, but it had no obvious effect on other coagulation factors, major anticoagulant factors or fibrinolytic indices. Our results suggest that zifaxaban had specific inhibitory effects on FXa and inhibited IVC thrombosis in rabbits with its hemorrhagic effect was less than that of rivaroxaban. Zifaxaban is ecpected to be developed as a new drug for the prevention of deep venous thrombosis, providing more medication options for patients with such disease, more research is required to support it in the future.


Assuntos
Inibidores do Fator Xa/farmacologia , Trombose/tratamento farmacológico , Veia Cava Inferior/patologia , Animais , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , China , Constrição Patológica , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Hemorragia/induzido quimicamente , Humanos , Coelhos , Rivaroxabana
4.
Eur J Pharmacol ; 836: 50-56, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30125563

RESUMO

Zifaxaban is an orally active, direct Factor Xa (FXa) inhibitor that is in development for the prevention and treatment of arterial and venous thrombosis. This study was conducted to investigate the biochemical and pharmacological activity of zifaxaban. In vitro activity was evaluated by enzyme, platelet aggregation, and clotting assays. In vivo effects were examined in venous thrombosis, arteriovenous-shunt thrombosis, carotid thrombosis, and bleeding models in rats. Zifaxaban competitively inhibits human FXa (IC50 = 11.1 nM) with > 10,000-fold greater selectivity than other serine proteases. It did not impair platelet aggregation induced by collagen, adenosine diphosphate (ADP) or arachidonic acid. It significantly prolonged clotting time, prothrombin time (PT), and activated partial thromboplastin time (APTT) in the plasma of humans, rabbits, and rats, with a relatively weak effect on thrombin time (TT). In venous thrombosis models in rats, zifaxaban strongly suppressed thrombus formation with ED50 values of 3.09 mg/kg, and its best efficacy time occurred at 2 h after administration. In arteriovenous-shunt thrombosis and carotid thrombosis models in rats, it inhibited thrombus formation in a dose-dependent manner. And in the rat tail bleeding assay, it showed a trend of less bleeding than rivaroxaban at doses that achieved the same antithrombotic effect. In conclusion, zifaxaban is a selective and direct FXa inhibitor and a promising oral anticoagulant for the prophylaxis and treatment of thromboembolic diseases.


Assuntos
Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacologia , Oxazóis/administração & dosagem , Oxazóis/farmacologia , Administração Oral , Animais , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/uso terapêutico , Feminino , Masculino , Oxazóis/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Wistar , Trombose Venosa/tratamento farmacológico
5.
Molecules ; 23(2)2018 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-29382075

RESUMO

In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a-1x and 1ha-1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 µM against human URAT1 for 1h vs. 7.18 µM and 0.28 µM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.


Assuntos
Metano/análogos & derivados , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ácido Úrico/metabolismo , Uricosúricos/síntese química , Benzobromarona/farmacologia , Transporte Biológico Ativo/efeitos dos fármacos , Radioisótopos de Carbono , Desenho de Fármacos , Expressão Gênica , Células HEK293 , Humanos , Metano/síntese química , Metano/farmacologia , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Relação Estrutura-Atividade , Tioglicolatos/farmacologia , Triazóis/farmacologia , Uricosúricos/farmacologia
6.
Biomed Rep ; 8(1): 77-84, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29387392

RESUMO

The aim of the present study was to investigate the efficacy of recombinant human prourokinase (rhPro-UK) on thromboembolic stroke in rabbits. A total of 210 rabbits were used in experiments. The 180 thromboembolic stroke rabbits were divided into three therapeutic time windows with six groups in each time window (n=10). The model group was administered saline, the reagent groups were administered rhPro-UK (2.5×, 5× and 10×104 U/kg), and the positive control groups were administered 5×104 urokinase (UK) U/kg and 4.5 mg/kg recombinant human tissue plasminogen activator via intravenous infusion at 3, 4.5 and 6 h after embolism. The remaining 30 rats (that had not undergone occlusion by autologous blood clots) served as a sham group and were administered saline. The radioactive intensity was detected using a medical gamma counter before and after the administration of the drug for 15, 30, 45, 60, 75, 90, 105 and 120 min. At 24 h after treatment, the brain samples were coronally sliced into 5 mm sections and hemorrhage was estimated used a semiquantitative method by counting the number of section faces with hemorrhaging. The plasma was collected for prothrombin time, activated partial thromboplastin time, fibrinogen and thrombin time tests using a solidification method with a blood coagulation factor analyzer. In addition, α2-antiplasmin (α2-AP) was evaluated using ELISA methods using a RT-6100 microplate reader. At the 3 h time point, the thrombolysis rate of rhPro-UK(2.5×, 5× and 10×104 U/kg) was 21.5% (P<0.05), 36.8% (P<0.001) and 55.0% (P<0.001), respectively together with patency rates of 10% (P>0.05), 40% (P<0.05) and 70% (P<0.001). Furthermore, α2-AP levels were reduced by 5.3% (P>0.05), 5.3% (P>0.05) and 18.1% (P<0.05). At the 4.5 h time point, the thrombolysis rate was 18.8% (P<0.05), 29.9% (P<0.01) and 49.0% (P<0.001) together with patency rates of 10% (P>0.05), 30% (P<0.05) and 50% (P<0.01), and α2-AP levels were reduced by 2.4% (P>0.05), 6.5% (P>0.05) and 17.8% (P<0.05). At the 6 h time point, the thrombolysis rate was 14.7% (P<0.05), 24.1%(P<0.01) and 35.7% (P<0.001) together with patency rates of 20% (P>0.05), 30% (P<0.05) and 40% (P<0.01), and α2-AP levels were reduced by 5.7% (P>0.05), 12.7% (P>0.05) and 22.2% (P<0.01). No significant differences (P>0.05) were identified between rhPro-UK (2.5×, 5× and 10×104 U/kg) and the model group regarding hemorrhage type, size and blood coagulation factors at the different time points. Thus, rhPro-UK promoted thrombolysis and recanalization (patency rate), with reduced risk of cerebral hemorrhage, and thus exerted protective effects on cerebral ischemia rabbits.

7.
Eur J Pharmacol ; 818: 429-434, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29154937

RESUMO

We evaluated the efficacy and safety of human recombinant prourokinase ( rhpro-UK) on thromboembolic stroke in rats. 60 rats with thromboembolic stroke were divided into 6 groups (n = 10). The model group was given saline, the reagent groups were given rhpro-UK (5, 10, 20 × 104U/kg), and positive control groups were given urokinase (UK) 10 × 104U/kg and recombinant tissue plasminogen activator (rt-PA) 9mg/kg through intravenous infusion at 1.5h after embolism. And other 10 rats without occluded by autologous blood clots as the sham group were given saline. At 6h after treatment, neurological deficit score and Magnetic Resonance Imaging(MRI) including T1WI and T2WI sequence scanning were measured. At 24h after treatment, the brain was cut for 2,3,5-triphenyltetrazolium chloride (TTC) staining and aspectrophotometric assay to measure the infarct area and intracerebral hemorrhage after neurological deficit detection. rhpro-UK (5, 10, 20 × 104 U/kg) improved neurological disorder by 39.1 ± 19.7% (n = 10, P > 0.05), 65.2 ± 14.2% (n = 10, P < 0.01) and 65.2 ± 14.2% (n = 10, P < 0.01) maximally; decreased brain lesion volume by 36.7 ± 34.8% (n = 10, P < 0.05), 77.6 ± 7.7% (n = 10, P < 0.01) and 80.5 ± 6.9% (n = 10, P < 0.01); decreased infarction area by 38.2 ± 24.0% (n = 10, P < 0.01), 73.9 ± 5.2% (n = 10, P < 0.001) and 79.7 ± 4.0% (n = 10, P < 0.001) respectively, and there were no statistics difference between rhpro-UK (5, 10, 20 × 104 U/kg) and each positive groups at intracerebral hemorrhage (P > 0.05). Rhpro-UK improved the damaged neural function, decreased the extent of the disease and did not raise bleeding, had protective effects for cerebral ischemia in rats.


Assuntos
Precursores Enzimáticos/farmacologia , Proteínas Recombinantes/farmacologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Tromboembolia/complicações , Ativador de Plasminogênio Tipo Uroquinase/farmacologia , Animais , Hemorragia Cerebral/complicações , Precursores Enzimáticos/uso terapêutico , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/uso terapêutico , Acidente Vascular Cerebral/patologia , Ativador de Plasminogênio Tipo Uroquinase/uso terapêutico
8.
Med Chem ; 13(3): 260-281, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27633583

RESUMO

BACKGROUND: Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy. OBJECTIVE: The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor. METHODS: The SAR of 1c was systematically explored and the in vitro URAT1 inhibitory activity of synthesized compounds 1a-1t was determined by the inhibition of URAT1-mediated [8-14C]uric acid uptake by human embryonic kidney 293 (HEK293) cells stably expressing human URAT1. RESULTS: Twenty compounds 1a-1t were synthesized. SAR analysis was performed. Two highly active URAT1 inhibitors, sodium 2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1j) and sodium 2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1m), were identified, which were 78- and 76-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay, respectively (IC50 values for 1j and 1m were 0.092 µM and 0.094 µM, respectively, against human URAT1 vs 7.18 µM for lesinurad). CONCLUSION: Two highly active URAT1 inhibitors were discovered. The SAR exploration also identified more flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for the design of URAT1 inhibitors, as indicated by the observation that many of the synthesized naphthyltriazolylmethane- bearing derivatives (1b-1d, 1g, 1j and 1m) showed significantly improved UART1 inhibitory activity (sub-micromolar IC50 values) as compared with lesinurad which has the rigid naphthyltriazole skeleton.


Assuntos
Descoberta de Drogas , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Compostos de Sulfidrila/farmacologia , Triazóis/farmacologia , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Triazóis/química
9.
Molecules ; 21(11)2016 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-27854343

RESUMO

In order to systematically explore and understand the structure-activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a-1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 µM against human URAT1 for 1q vs 7.18 µM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.


Assuntos
Ácido Butírico/química , Ácido Butírico/farmacologia , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ácido Butírico/síntese química , Linhagem Celular , Técnicas de Química Combinatória , Humanos , Concentração Inibidora 50 , Estrutura Molecular
10.
Sci Rep ; 5: 18039, 2015 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-26658631

RESUMO

The multiple physiological properties of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of type 2 diabetes. However, the in vivo half-life of GLP-1 is short due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The poor stability of GLP-1 has significantly limited its clinical utility; however, many studies are focused on extending its stability. Fatty acid conjugation is a traditional approach for extending the stability of therapeutic peptides because of the high binding affinity of human serum albumin for fatty acids. However, the conjugate requires a complex synthetic approach, usually involving Lys and occasionally involving a linker. In the current study, we conjugated the GLP-1 molecule with fatty acid derivatives to simplify the synthesis steps. Human serum albumin binding assays indicated that the retained carboxyl groups of the fatty acids helped maintain a tight affinity to HSA. The conjugation of fatty acid-like molecules improved the stability and increased the binding affinity of GLP-1 to HSA. The use of fatty acid-like molecules as conjugating components allowed variant conjugation positions and freed carboxyl groups for other potential uses. This may be a novel, long-acting strategy for the development of therapeutic peptides.


Assuntos
Ácidos Graxos/metabolismo , Peptídeos/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Dipeptidil Peptidase 4/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Meia-Vida , Humanos , Masculino , Camundongos , Precursores de Proteínas/metabolismo , Ratos , Albumina Sérica/metabolismo
11.
Drug Des Devel Ther ; 8: 1839-49, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25342883

RESUMO

Self-assembling peptides are capable of forming a complex containing a cavity where cytotoxic agents can be wrapped in a self-assembling manner. These complexes are beneficial for improving the pharmacological properties and pharmacokinetics of cytotoxic agents, such as doxorubicin and paclitaxel. In the present study, this self-assembling feature was successfully integrated into a hexapeptide with matrix metalloproteinase (MMP)-2 specific targeting activity, producing a supramolecule possessing controlled drug release characteristics. The MMP-2 specific substrate fragment, PVGLIG, makes this supramolecule disassociate in the presence of MMP-2, and this system is considered to be a powerful tool for the treatment of tumors with high expression of MMP-2 or tumor metastasis. Our findings show that this modified self-assembling peptide with the PVGLIG fragment was able to significantly enhance specificity against HT1080 cells, a tumor cell line with high expression of MMP-2. In addition, residence time of the complex in blood was prolonged since paclitaxel was wrapped into the supramolecule. Our results suggest that the modified MMP-2 specific substrate, SAMTA7, could act as a controlled and sustained drug carrier for treatment of tumors with high expression of MMP-2 and for tumor metastasis.


Assuntos
Sistemas de Liberação de Medicamentos , Metaloproteinase 2 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Fragmentos de Peptídeos/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Inibidores de Metaloproteinases de Matriz/química , Camundongos , Camundongos Endogâmicos DBA , Simulação de Dinâmica Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Relação Estrutura-Atividade
12.
Med Chem ; 10(3): 304-17, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24059684

RESUMO

Systematic mono-deoxylation of the four hydroxyl groups in the glucose moiety in dapagliflozin led to the discovery of 6-deoxydapagliflozin 1 as a more active sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor (IC50 = 0.67 nM against human SGLT2 (hSGLT2) vs 1.16 nM for dapagliflozin). It exhibited more potent blood glucose inhibitory activity in rat oral glucose tolerance test and induced more urinary glucose in rat urinary glucose excretion test than its parent compound dapagliflozin.


Assuntos
Compostos Benzidrílicos/farmacologia , Desoxiglucose/análogos & derivados , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/química , Glicemia/efeitos dos fármacos , Desoxiglucose/administração & dosagem , Desoxiglucose/química , Desoxiglucose/farmacologia , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Estrutura Molecular , Ratos , Transportador 2 de Glucose-Sódio , Relação Estrutura-Atividade
13.
Curr Pharm Biotechnol ; 14(9): 835-41, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24372261

RESUMO

The outstanding physiological functions of glucagon-like peptide-1 make it a promising drug candidate for blood glucose regulation in type 2 diabetes. However, the short half-life of GLP-1 limited its widely clinical utility due to the rapid degradation by dipeptidyl peptidase IV (DPP-IV) and renal clearance. Therefore, stabilisation of glucagon-like peptide-1 is critical for the use of this peptide in drug development. Scientists in pharmaceutical companies have contributed in years to obtain long-acting or sustained GLP-1 derivatives which are reviewed in this report.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hipoglicemiantes/uso terapêutico , Animais , Preparações de Ação Retardada , Peptídeo 1 Semelhante ao Glucagon/química , Humanos , Hipoglicemiantes/química , Relação Estrutura-Atividade
14.
J Med Chem ; 56(18): 7212-21, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-23957426

RESUMO

Activating mutations of PTPN11 (encoding the SHP2 phosphatase) are associated with Noonan syndrome, childhood leukemias, and sporadic solid tumors. Virtual screening combined with experimental assays was performed to identify inhibitors of SHP2 from a database of natural products. This effort led to the identification of cryptotanshinone as an inhibitor of SHP2. Cryptotanshinone inhibited SHP2 with an IC50 of 22.50 µM. Fluorescence titration experiments confirmed that it directly bound to SHP2. Enzymatic kinetic analyses showed that cryptotanshinone was a mixed-type and irreversible inhibitor. This drug was further verified for its ability to block SHP2-mediated cell signaling and cellular functions. Furthermore, mouse myeloid progenitors and patient leukemic cells with the activating mutation E76K in PTPN11 were found to be sensitive to this inhibitor. Since cryptotanshinone is used to treat cardiovascular diseases in Asian countries, this drug has a potential to be used directly or to be further developed to treat PTPN11-associated malignancies.


Assuntos
Inibidores Enzimáticos/farmacologia , Fenantrenos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Desenho Assistido por Computador , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Humanos , Camundongos , Modelos Moleculares , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo
15.
Mol Cancer Ther ; 12(9): 1738-48, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23825065

RESUMO

Activating mutations in PTPN11 (encoding SHP2), a protein tyrosine phosphatase (PTP) that plays an overall positive role in growth factor and cytokine signaling, are directly associated with the pathogenesis of Noonan syndrome and childhood leukemias. Identification of SHP2-selective inhibitors could lead to the development of new drugs that ultimately serve as treatments for PTPN11-associated diseases. As the catalytic core of SHP2 shares extremely high homology to those of SHP1 and other PTPs that play negative roles in cell signaling, to identify selective inhibitors of SHP2 using computer-aided drug design, we targeted a protein surface pocket that is adjacent to the catalytic site, is predicted to be important for binding to phosphopeptide substrates, and has structural features unique to SHP2. From computationally selected candidate compounds, #220-324 effectively inhibited SHP2 activity with an IC50 of 14 µmol/L. Fluorescence titration experiments confirmed its direct binding to SHP2. This active compound was further verified for its ability to inhibit SHP2-mediated cell signaling and cellular function with minimal off-target effects. Furthermore, mouse myeloid progenitors with the activating mutation (E76K) in PTPN11 and patient leukemic cells with the same mutation were more sensitive to this inhibitor than wild-type cells. This study provides evidence that SHP2 is a "druggable" target for the treatment of PTPN11-associated diseases. As the small-molecule SHP2 inhibitor identified has a simple chemical structure, it represents an ideal lead compound for the development of novel anti-SHP2 drugs. Mol Cancer Ther; 12(9); 1738-48. ©2013 AACR.


Assuntos
Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Leucemia Mieloide/patologia , Síndrome de Noonan/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Triazinas/farmacologia , Animais , Domínio Catalítico/efeitos dos fármacos , Domínio Catalítico/genética , Linhagem Celular , Criança , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/química , Técnicas de Inativação de Genes , Humanos , Indóis/química , Indóis/metabolismo , Leucemia Mieloide/tratamento farmacológico , Camundongos , Estrutura Molecular , Mutação , Síndrome de Noonan/tratamento farmacológico , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Triazinas/química , Triazinas/metabolismo , Células Tumorais Cultivadas
16.
Acta Crystallogr Sect E Struct Rep Online ; 68(Pt 10): o2850, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23125653

RESUMO

The title compound, C(15)H(20)O(2), crystallizes with two independent mol-ecules of similar geometry in the asymmetric unit. The cyclo-hexyl ring adopts a chair conformation in each mol-ecule. In the crystal, mol-ecules related by translation are linked into chains along the a axis via weak C-H⋯O inter-actions.

17.
Diabetes Res Clin Pract ; 96(3): 362-70, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22284602

RESUMO

The multiple physiological characterizations of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the therapy of type 2 diabetes. However, the biological half-life of GLP-1 is short in vivo due to degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The stabilization of GLP-1 is critical for its utility in drug development. In this study, several GLP-1 mutants containing an N-terminal cyclic conformation were prepared in that the existence of cyclic conformation is predicted to increase the stabilization of GLP-1 in vivo. In this study, the binding capacities of the mutants were determined, the stabilities of the mutants were investigated and the physiological functions of the mutants were compared with those of wild-type GLP-1 in animals. The results indicated that the mutant (GLP1N8) remarkably raised the half-life in vivo; it also showed better glucose tolerance and higher HbA(1c) reduction than GLP-1 and exendin-4 in rodents. These results suggest that the GLP-1 analog (GLP1N8) which contains an N-terminal cyclic structure might be utilized as possible potent anti-diabetic drugs in the treatment of type 2 diabetes mellitus.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Dipeptidil Peptidase 4/farmacologia , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Hemoglobina A Glicada/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Teste de Tolerância a Glucose , Meia-Vida , Injeções Subcutâneas , Masculino , Ratos
18.
Bioorg Med Chem Lett ; 22(1): 110-4, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22169262

RESUMO

We report herein the design and synthesis of novel 4-aminoquinazoline derivatives based on the inhibitors of VEGFR-2 tyrosine kinases. The VEGFR-2 inhibitory activities of these newly synthesized compounds were also evaluated and compared with that of ZD6474. We found that most of target compounds had good inhibitory potency. In particular, compounds 1h, 1n and 1o were found to be 6, 2 and 2-fold more potent than the positive control ZD6474. The leading compound 1h also showed an in vivo activity against HepG2 human tumor xenograft model in BALB/c-nu mice.


Assuntos
Química Farmacêutica/métodos , Quinazolinas/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Inibidores Enzimáticos/farmacologia , Células Hep G2 , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Modelos Químicos , Transplante de Neoplasias , Piperidinas/farmacologia , Quinazolinas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química
19.
Diabetes Res Clin Pract ; 93(3): 410-20, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21641071

RESUMO

The multiple physiological characterizations of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of type 2 diabetes. However, in vivo, the half-life of GLP-1 is short, which is caused by the degradation of dipeptidyl peptidase-IV (DPP-IV) and renal clearance. Thus, the stabilization of GLP-1 is critical for its utility in drug development. Peptides known as GLP-1 protectors are predicted to increase the half-life of GLP-1 in vivo. Protecting peptides are able to form stable complexes by non-covalent interactions with human GLP-1. In this study, the stability of the complex was investigated, and the physiological functions of the GLP-1/peptide 1 complex were compared to those of exenatide and liraglutide in animals. The results indicated that the GLP-1/peptide 1 complex remarkably raised the half-life of GLP-1 in vivo and showed better glucose tolerance and higher HbA(1c) reduction than exenatide and liraglutide in rodents. Based upon these results, it is suggested that the GLP-1/peptide 1 complex might be utilized as a possible potent anti-diabetic drug in the treatment of type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hipoglicemiantes/uso terapêutico , Peptídeos/uso terapêutico , Animais , Cromatografia Líquida de Alta Pressão , Exenatida , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/química , Humanos , Hipoglicemiantes/química , Liraglutida , Masculino , Peptídeos/química , Ratos , Espectrometria de Massas por Ionização por Electrospray , Peçonhas/uso terapêutico
20.
Peptides ; 32(7): 1408-14, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21664938

RESUMO

The multiple physiological characterizations of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the therapy of type 2 diabetes. However, the half-life of GLP-1 is short in vivo due to degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. Therefore, the stabilization of GLP-1 is critical for its utility in drug development. Based on our previous research, a GLP-1 analog that contained an intra-disulfide bond exhibited a prolonged biological half-life. In this study, we improved upon previous analogs with a novel GLP-1 analog that contained a tryptophan cage-like sequence for an improved binding affinity to the GLP-1 receptor. The binding capacities and the stabilities of GLP715a were investigated, and the physiological functions of the GLP715a were compared to those of the wild-type GLP-1 in animals. The results demonstrated that the new GLP-1 analog (GLP715a) increased its biological half-life to approximately 48h in vivo; GLP715a also exhibited a higher binding affinity to the GLP-1 receptor than the wild-type GLP-1. The increased binding capacity of GLP715a to its receptor resulted in a quick response to glucose administration. The long-acting anti-diabetic property of GLP715a was revealed by its increased glucose tolerance, higher HbA(1c) reduction, more efficient glucose clearance and quicker insulin stimulation upon glucose administration compared to the wild-type GLP-1 in rodents. The improved physiological characterizations of GLP715a make it a possible potent anti-diabetic drug in the treatment of type 2 diabetes mellitus.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Peptídeo 1 Semelhante ao Glucagon , Hipoglicemiantes , Insulina/sangue , Receptores de Glucagon/metabolismo , Triptofano/metabolismo , Sequência de Aminoácidos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Dipeptidil Peptidase 4/metabolismo , Estabilidade de Medicamentos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/síntese química , Peptídeo 1 Semelhante ao Glucagon/farmacocinética , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1 , Teste de Tolerância a Glucose , Hemoglobina A Glicada/análise , Meia-Vida , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Cinética , Masculino , Dados de Sequência Molecular , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Soro/química , Soro/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Triptofano/química
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