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1.
ACS Med Chem Lett ; 13(8): 1248-1254, 2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-35978682

RESUMO

Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments. We have demonstrated that concomitant activation GLP1R and the glucagon receptor (GCGR) can improve glucose metabolism and provide superior weight loss when compared to selective GLP1R agonism in preclinical species. This paper will highlight chemistry structure-activity relationship optimization and summarize in vivo efficacy studies toward the discovery of a once daily balanced dual agonist 12 (MK-1462), which was advanced into clinical trials.

2.
Bioorg Med Chem Lett ; 30(15): 127279, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32527459

RESUMO

The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.


Assuntos
Descoberta de Drogas , Fator IXa/antagonistas & inibidores , Inibidores do Fator Xa/farmacologia , Pirimidinas/farmacologia , Relação Dose-Resposta a Droga , Fator IXa/metabolismo , Inibidores do Fator Xa/síntese química , Inibidores do Fator Xa/química , Humanos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 30(16): 127072, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32340773

RESUMO

A series of 4, 4-disubstituted proline analogs were designed, synthesized, and tested for selective inhibition of blood coagulation factor XIa in search of new non-vitamin K antagonists based oral anticoagulants for potential prevention and treatment of thrombotic diseases. Starting from a potent thrombin (FIIa) inhibitor chemotype with FIIa IC50 = 1 nM and FXIa IC50 = 160 nM, medicinal chemistry iterations guided by molecular modeling and structure-based drug design led to steady improvement of FXIa potency while dialing down thrombin activity and improving selectivity. Through this exercise, a thousand-fold enhancement of selectivity over thrombin was achieved with some analogs carrying factor XIa inhibition potencies in the 10 nM range. In this communication, we discuss the design principles and structure activity relationship (SAR) of these novel FXIa selective inhibitors.


Assuntos
Anticoagulantes/farmacologia , Desenho de Fármacos , Fator XIa/antagonistas & inibidores , Prolina/farmacologia , Anticoagulantes/síntese química , Anticoagulantes/química , Relação Dose-Resposta a Droga , Fator XIa/metabolismo , Humanos , Estrutura Molecular , Prolina/síntese química , Prolina/química , Relação Estrutura-Atividade
4.
ACS Med Chem Lett ; 9(5): 457-461, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29795759

RESUMO

The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPCR target at which agonists have demonstrated glucose-dependent insulin secretion and shows beneficial effects on glycemic control. Herein, we describe our efforts leading to the identification of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose tolerance in multiple animal models and has excellent off-target profile. The key design elements in the compounds involved a combination of a fluoro-pyrimidine and a conformationally constrained bridged piperidine to impart good potency and efficacy.

5.
Sci Rep ; 8(1): 585, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29330364

RESUMO

A promising emerging area for the treatment of obesity and diabetes is combinatorial hormone therapy, where single-molecule peptides are rationally designed to integrate the complementary actions of multiple endogenous metabolically-related hormones. We describe here a proof-of-concept study on developing unimolecular polypharmacy agents through the use of selection methods based on phage-displayed peptide libraries (PDL). Co-agonists of the glucagon (GCG) and GLP-1 receptors were identified from a PDL sequentially selected on GCGR- and GLP1R-overexpressing cells. After two or three rounds of selection, 7.5% of randomly picked clones were GLP1R/GCGR co-agonists, and a further 1.53% were agonists of a single receptor. The phages were sequenced and 35 corresponding peptides were synthesized. 18 peptides were potent co-agonists, 8 of whom showed EC50 ≤ 30 pM on each receptor, comparable to the best rationally designed co-agonists reported in the literature. Based on literature examples, two sequences were engineered to stabilize against dipeptidyl peptidase IV cleavage and prolong the in vivo half-life: the engineered peptides were comparably potent to the parent peptides on both receptors, highlighting the potential use of phage-derived peptides as therapeutic agents. The strategy described here appears of general value for the discovery of optimized polypharmacology paradigms across several metabolically-related hormones.


Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos/síntese química , Peptídeos/farmacologia , Receptores de Glucagon/agonistas , Diabetes Mellitus/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Humanos , Obesidade/tratamento farmacológico , Biblioteca de Peptídeos , Peptídeos/genética , Polimedicação , Análise de Sequência de DNA
6.
Bioorg Med Chem Lett ; 25(22): 5291-4, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26433449

RESUMO

The design and synthesis of two conformationally restricted oxazabicyclo octane derivatives as GRP119 agonists is described. Derivatives of scaffold C, with syn configuration, have the best overall profiles with respect to solubility and in vivo efficacy. Compound 25a was found to have extremely potent agonistic activity and was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test at a dose of 0.1 mg/kg.


Assuntos
Compostos Azabicíclicos/síntese química , Hipoglicemiantes/síntese química , Pirimidinas/síntese química , Receptores Acoplados a Proteínas G/agonistas , Animais , Compostos Azabicíclicos/farmacologia , Teste de Tolerância a Glucose , Células HEK293 , Humanos , Hipoglicemiantes/farmacologia , Camundongos , Pirimidinas/farmacologia , Solubilidade
7.
Eur J Pharmacol ; 762: 221-8, 2015 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-26022529

RESUMO

Vorapaxar is a novel protease-activated receptor-1 (PAR1) antagonist recently approved for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or with peripheral arterial disease. The present study provides a comprehensive in vitro pharmacological characterization of vorapaxar interaction with the PAR1 receptor on human platelets. Similar studies were performed with a metabolite of vorapaxar (M20). Vorapaxar and M20 were competitive PAR1 antagonists that demonstrated concentration-dependent, saturable, specific, and slowly reversible binding to the receptor present on intact human platelets. The affinities of vorapaxar and M20 for the PAR1 receptor were in the low nanomolar range, as determined by saturation-, kinetic- and competitive binding studies. The calculated Kd and Ki values for vorapaxar increased in the presence of plasma, indicating a decrease in the free fraction available for binding to the PAR1 receptor on human platelets. Vorapaxar was also evaluated in functional assays using thrombin or a PAR1 agonist peptide (SFLLRN). Vorapaxar and M20 completely blocked thrombin-stimulated PAR1/ß-arrestin association in recombinant cells and abolished thrombin-stimulated calcium influx in washed human platelets and vascular smooth muscle cells. Moreover, vorapaxar and M20 inhibited PAR1 agonist peptide-mediated platelet aggregation in human platelet rich plasma with a steep concentration response relationship. Vorapaxar exhibited high selectivity for inhibition of PAR1 over other platelet GPCRs. In conclusion, vorapaxar is a potent PAR1 antagonist exhibiting saturable, reversible, selective binding with slow off-rate kinetics and effectively inhibits thrombin's PAR1-mediated actions on human platelets.


Assuntos
Plaquetas/efeitos dos fármacos , Lactonas/farmacologia , Piridinas/farmacologia , Receptor PAR-1/antagonistas & inibidores , Arrestinas/metabolismo , Ligação Competitiva , Plaquetas/metabolismo , Plaquetas/fisiologia , Proteínas Sanguíneas/metabolismo , Cálcio/metabolismo , Humanos , Cinética , Lactonas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Piridinas/metabolismo , Receptor PAR-1/metabolismo , Especificidade por Substrato , beta-Arrestinas
8.
ACS Med Chem Lett ; 6(5): 553-7, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-26005532

RESUMO

Modification of the previously disclosed (S)-N-(2-(aminomethyl)-5-chlorobenzyl)-1-((R)-2-hydroxy-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide 2 by optimization of the P3 group afforded novel, low molecular weight thrombin inhibitors. Heterocycle replacement of the hydroxyl functional group helped maintain thrombin in vitro potency while improving the chemical stability and pharmacokinetic profile. These modifications led to the identification of compound 10, which showed excellent selectivity over related serine proteases as well as in vivo efficacy in the rat arteriovenous shunt. Compound 10 exhibited significantly improved chemical stability and pharmacokinetic properties over 2 and may be utilized as a structurally differentiated preclinical tool comparator to dabigatran etexilate (Pro-1) to interrogate the on- and off-target effects of oral direct thrombin inhibitors.

9.
Drug Discov Today ; 19(9): 1435-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24794465

RESUMO

Prevention and treatment of thromboembolic disorders with minimal bleeding risk remains a significant unmet medical need. Studies in Factor XI (FXI)-deficient humans and experimental animal models suggest that targeting FXI in humans provides antithrombotic benefits with reduced bleeding liability compared with current standard of care. In this review, we describe an exciting era in the discovery and development of antithrombotic agents as multiple therapeutic modalities for FXI(a) inhibition progress through preclinical and clinical development.


Assuntos
Fator XI/antagonistas & inibidores , Fibrinolíticos/farmacologia , Tromboembolia/tratamento farmacológico , Animais , Modelos Animais de Doenças , Desenho de Fármacos , Descoberta de Drogas/métodos , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Tromboembolia/prevenção & controle
10.
Bioorg Med Chem Lett ; 21(11): 3290-6, 2011 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-21536438

RESUMO

The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure-activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hiperglicemia/tratamento farmacológico , Nortropanos/síntese química , Receptores Acoplados a Proteínas G/agonistas , Administração Oral , Animais , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Concentração Inibidora 50 , Camundongos , Nortropanos/química , Nortropanos/uso terapêutico , Ratos
11.
J Med Chem ; 51(3): 581-8, 2008 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-18198821

RESUMO

Melanin-concentrating hormone receptor 1 (MCH-R1) is a G-protein-coupled receptor (GPCR) and a target for the development of therapeutics for obesity. The structure-based development of MCH-R1 and other GPCR antagonists is hampered by the lack of an available experimentally determined atomic structure. A ligand-steered homology modeling approach has been developed (where information about existing ligands is used explicitly to shape and optimize the binding site) followed by docking-based virtual screening. Top scoring compounds identified virtually were tested experimentally in an MCH-R1 competitive binding assay, and six novel chemotypes as low micromolar affinity antagonist "hits" were identified. This success rate is more than a 10-fold improvement over random high-throughput screening, which supports our ligand-steered method. Clearly, the ligand-steered homology modeling method reduces the uncertainty of structure modeling for difficult targets like GPCRs.


Assuntos
Ligantes , Modelos Moleculares , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Receptores do Hormônio Hipofisário/química , Receptores de Somatostatina/antagonistas & inibidores , Receptores de Somatostatina/química , Animais , Sítios de Ligação , Ligação Competitiva , Células CHO , Bovinos , Cricetinae , Cricetulus , Bases de Dados Factuais , Humanos , Receptores do Hormônio Hipofisário/metabolismo , Receptores de Somatostatina/metabolismo , Rodopsina/química , Homologia de Sequência de Aminoácidos , Processos Estocásticos , Relação Estrutura-Atividade , Termodinâmica
12.
Bioorg Med Chem Lett ; 17(17): 4845-50, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17604169

RESUMO

To address the hERG liability of MCHR1 antagonists such as 1 and 2, new analogs such as 4 and 5 that incorporated a polar heteroaryl group were designed and synthesized. Biological evaluation confirmed that these new analogs retained MCH R1 activity with greatly attenuated hERG liabilities as indicated in the Rb efflux assay.


Assuntos
Química Farmacêutica/métodos , Heptanos/química , Hexanos/química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Peixes , Humanos , Cinética , Camundongos , Modelos Químicos , Estrutura Molecular , Obesidade/tratamento farmacológico
13.
Bioorg Med Chem ; 15(16): 5369-85, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17572094

RESUMO

To improve the ex vivo potency of MCH inhibitor 1a and to address its hERG liability, a structure-activity study was carried out, focusing on three regions of the lead structure. Introduction of new side chains with basic nitrogen improved in vitro and ex vivo bindings. Many potent compounds with K(i)<10nM were discovered (compounds 6a-j) and several compounds (14-17) had excellent ex vivo binding at 6h and 24h. Attenuating the basicity of nitrogen on the side chain, and in particular, introduction of a polar group such as aminomethyl on the distal phenyl ring significantly lowered the hERG activity. Further replacement of the distal phenyl group with heteroaryl groups in the cyclohexene series provided compounds such as 28l with excellent ex vivo activity with much reduced hERG liability.


Assuntos
Cicloeptanos/química , Cicloeptanos/farmacocinética , Proteínas de Ligação a DNA/metabolismo , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Transativadores/metabolismo , Animais , Camundongos , Estrutura Molecular , Receptores do Hormônio Hipofisário/metabolismo , Relação Estrutura-Atividade , Regulador Transcricional ERG
14.
Mol Pharmacol ; 71(1): 19-29, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17005902

RESUMO

Ezetimibe is the first in class 2-azetidinone that decreases plasma cholesterol by blocking intestinal cholesterol absorption. Ezetimibe effectively reduces plasma cholesterol in several species including human, monkey, dog, hamster, rat, and mouse, but the potency ranges widely. One potential factor responsible for this variation in responsiveness is diversity in ezetimibe metabolism. After oral administration, ezetimibe is glucuronidated. Both ezetimibe and the glucuronide lower plasma cholesterol; however, the glucuronide exhibits greater potency. Recent identification of Niemann-Pick C1 Like-1 (NPC1L1) as the molecular target of ezetimibe enables direct binding studies to be performed. Here, we report the cloning of NPC1L1 derived from multiple species and assess amino acid sequence homology among human, monkey, dog, hamster, rat, and mouse. The rank order of affinity of glucuronidated ezetimibe for NPC1L1 in each species correlates with the rank order of in vivo activity with monkey > dog > hamster and rat >> mouse. Ezetimibe analogs that bind to NPC1L1 exhibit in vivo cholesterol-lowering activity, whereas compounds that do not bind NPC1L1 are inactive. Specific structural components of ezetimibe are identified as critical for binding to NPC1L1. The results demonstrate that small variations in ezetimibe structure or in NPC1L1 amino acid sequence can profoundly influence ezetimibe/NPC1L1 interaction and consequently in vivo activity. The results demonstrate that the ability of compounds to bind to NPC1L1 is the major determinant of in vivo responsiveness.


Assuntos
Azetidinas/farmacologia , Azetidinas/farmacocinética , Proteínas de Membrana/fisiologia , Sequência de Aminoácidos , Animais , Anticolesterolemiantes/farmacologia , Sítios de Ligação , Células Cultivadas , Colesterol/metabolismo , Clonagem Molecular , DNA Complementar/genética , Ezetimiba , Humanos , Absorção Intestinal , Proteínas de Membrana/química , Proteínas de Membrana/genética , Proteínas de Membrana Transportadoras , Modelos Moleculares , Dados de Sequência Molecular , Doenças de Niemann-Pick , Conformação Proteica , Ratos
16.
Bioorg Med Chem Lett ; 16(16): 4262-5, 2006 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-16753297

RESUMO

Herein, we report the discovery of an effective strategy to modulate liabilities related to affinity of previously disclosed bicyclohexane MCHR-1 antagonists for the hERG channel. This paper describes one of several strategies incorporated to limit hERG binding via modifications of a terminal aryl group in an otherwise promising bicyclohexyl urea series.


Assuntos
Canais de Potássio Éter-A-Go-Go/metabolismo , Melaninas/química , Receptores de Somatostatina/antagonistas & inibidores , Ureia/farmacologia , Química Farmacêutica , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Cinética , Modelos Químicos , Ligação Proteica , Ureia/química
17.
Bioorg Med Chem Lett ; 16(14): 3668-73, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16690312

RESUMO

Isosteric replacement of the urea group of lead compound 1 led to novel substituted piperidine phenylamide analogues. SAR on the electron-induced effects of various linkers as well as substituents on the phenyl rings and the piperidine nitrogen has been investigated. Many single-digit nanomolar MCH R1 antagonists have been identified from this series.


Assuntos
Piperidinas/síntese química , Piperidinas/farmacologia , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Humanos , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 16(14): 3674-8, 2006 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-16690315

RESUMO

Biaryl urea lead compound 1 was discovered earlier in our MCH antagonist program. Novel benzimidazole analogues with increased chemical stability, devoid of the potential carcinogenic liability associated with a biarylamine moiety, were synthesized and evaluated to be potent MCH R1 antagonists. Two compounds in this series have demonstrated in vivo efficacy in a rodent obesity model.


Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Peso Corporal/efeitos dos fármacos , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Administração Oral , Animais , Modelos Animais de Doenças , Desenho de Fármacos , Ratos , Relação Estrutura-Atividade
19.
J Med Chem ; 49(7): 2294-310, 2006 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-16570926

RESUMO

Melanin-concentrating hormone (MCH) is a cyclic, nonadecapeptide expressed in the CNS of all vertebrates that regulates feeding behavior and energy homeostasis via interaction with the central melanocortin system. Regulation of this interaction results in modulation of food intake and body weight gain, demonstrating significant therapeutic potential for the treatment of obesity. The MCH-1 receptor (MCH-R1) has been identified as a key target in MCH regulation, as small molecule antagonists of MCH-R1 have demonstrated activity in vivo. Herein, we document our research in a bicyclo[3.1.0]hexyl urea series with particular emphasis on structure-activity relationships and optimization of receptor occupancy, measured both in vitro and via an ex vivo binding assay following an oral dosing regimen. Several compounds have been tested in vivo and exhibit oral efficacy in relevant acute rodent feeding models. In particular, 24u has proven efficacious in chronic rodent models of obesity, showing a statistically significant reduction in food intake and body weight over a 28 day study.


Assuntos
Fármacos Antiobesidade/síntese química , Compostos de Fenilureia/síntese química , Piperazinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Administração Oral , Animais , Fármacos Antiobesidade/farmacologia , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Ingestão de Alimentos/efeitos dos fármacos , Meia-Vida , Masculino , Obesidade/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Distribuição Tecidual , Ureia/farmacologia
20.
Eur J Pharmacol ; 535(1-3): 182-91, 2006 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-16540104

RESUMO

Melanin concentrating hormone (MCH) is a cyclic neuropeptide expressed in the lateral hypothalamus that plays an important role in energy homeostasis. To investigate the pharmacological consequences of inhibiting MCH signaling in murine obesity models, we examined the effect of acute and chronic administration of a selective MCH1 receptor antagonist (SCH-A) in diet-induced obese (DIO) and Lep(ob/ob) mice. Oral administration of SCH-A for 5 consecutive days (30 mg/kg q.d.) produced hypophagia, a loss of body weight and adiposity, and decreased plasma leptin levels in DIO mice, and hypophagia and reduced weight gain in Lep(ob/ob) mice. Chronic administration of SCH-A to DIO mice decreased food intake, body weight and adiposity, and plasma leptin and free fatty acids. These effects were accompanied by increases in several hypothalamic neuropeptides. Acute administration of SCH-A (30 mg/kg) prevented the decrease in energy expenditure associated with food restriction. These results indicate that MCH1 receptor antagonists may be effective in the treatment of obesity.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Nitrilas/farmacologia , Obesidade/fisiopatologia , Piperazinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Tecido Adiposo/efeitos dos fármacos , Administração Oral , Animais , Ligação Competitiva , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Gorduras na Dieta/administração & dosagem , Relação Dose-Resposta a Droga , Ácidos Graxos não Esterificados/sangue , Feminino , Galanina/genética , Expressão Gênica/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Hormônios Hipotalâmicos/genética , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Insulina/sangue , Peptídeos e Proteínas de Sinalização Intracelular/genética , Radioisótopos do Iodo , Leptina/sangue , Masculino , Melaninas/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neuropeptídeo Y/genética , Neuropeptídeos/genética , Nitrilas/administração & dosagem , Obesidade/etiologia , Oligopeptídeos/metabolismo , Receptores de Orexina , Orexinas , Piperazinas/administração & dosagem , Hormônios Hipofisários/genética , Ligação Proteica , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos , Receptores de Somatostatina/genética , Receptores de Somatostatina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Triglicerídeos/sangue , Ureia/administração & dosagem , Ureia/farmacologia
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