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1.
J Med Chem ; 66(18): 13135-13147, 2023 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-37724542

RESUMO

A series of dihydropyridinone (DHP) compounds was prepared and evaluated for MGAT2 activity. The efforts led to the identification of novel tetrazolones with potent MGAT2 inhibitory activity and favorable in vitro profiles. Further tests of select analogues in mouse models revealed significant reduction in food intake and body weight. Subsequent studies in MGAT2 knockout mice with the lead candidate 12 (BMS-986172) showed on-target- and mechanism-based pharmacology. Moreover, its favorable pharmacokinetic (PK) profile and the lack of species variability in the glucuronidation potential resulted in a greater confidence level in the projection of a low dose for achieving targeted efficacious exposures in humans. Consistent with these projections, PK data from a phase 1 trial confirmed that targeted efficacious exposures could be achieved at a low dose in humans, which supported compound 12 as our second and potentially superior development candidate for the treatment of various metabolic disorders.


Assuntos
Doenças Metabólicas , Piridonas , Animais , Humanos , Camundongos , Peso Corporal , Doenças Metabólicas/tratamento farmacológico , Piridonas/química , Piridonas/farmacologia , N-Acetilglucosaminiltransferases/antagonistas & inibidores
2.
Bioorg Med Chem Lett ; 91: 129362, 2023 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-37295614

RESUMO

Inhibition of monoacylglycerol transferase 2 (MGAT2) has recently emerged as a potential therapeutic strategy for the treatment of metabolic diseases such as obesity, diabetes and non-alcoholic steatohepatitis (NASH). Metabolism studies with our clinical lead (1) suggested variability in in vitro glucuronidation rates in liver microsomes across species, which made projection of human doses challenging. In addition, the observation of deconjugation of the C3-C4 double bond in the dihydropyridinone ring of 1 in solution had the potential to complicate its clinical development. This report describes our lead optimization efforts in a novel pyridinone series, exemplified by compound 33, which successfully addressed both of these potential issues.


Assuntos
Doenças Metabólicas , Monoglicerídeos , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/química , Obesidade/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico
3.
Cell Metab ; 34(11): 1732-1748.e5, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36323235

RESUMO

Monoacylglycerol acyltransferase 2 (MGAT2) is an important enzyme highly expressed in the human small intestine and liver for the regulation of triglyceride absorption and homeostasis. We report that treatment with BMS-963272, a potent and selective MGAT2 inhibitor, decreased inflammation and fibrosis in CDAHFD and STAM, two murine nonalcoholic steatohepatitis (NASH) models. In high-fat-diet-treated cynomolgus monkeys, in contrast to a selective diacylglycerol acyltransferase 1 (DGAT1) inhibitor, BMS-963272 did not cause diarrhea. In a Phase 1 multiple-dose trial of healthy human adults with obesity (NCT04116632), BMS-963272 was safe and well tolerated with no treatment discontinuations due to adverse events. Consistent with the findings in rodent models, BMS-963272 elevated plasma long-chain dicarboxylic acid, indicating robust pharmacodynamic biomarker modulation; increased gut hormones GLP-1 and PYY; and decreased body weight in human subjects. These data suggest MGAT2 inhibition is a promising therapeutic opportunity for NASH, a disease with high unmet medical needs.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Obesidade , Animais , Humanos , Camundongos , Peso Corporal , Inflamação/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , Adulto , Ensaios Clínicos Fase I como Assunto
4.
J Med Chem ; 65(13): 8948-8960, 2022 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-35704802

RESUMO

While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares
5.
Rheumatology (Oxford) ; 61(4): 1717-1727, 2022 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-34289031

RESUMO

OBJECTIVE: SSc is a rheumatic autoimmune disease affecting roughly 20 000 people worldwide and characterized by excessive collagen accumulation in the skin and internal organs. Despite the high morbidity and mortality associated with SSc, there are no approved disease-modifying agents. Our objective in this study was to explore transcriptomic and model-based drug discovery approaches for SSc. METHODS: In this study, we explored the molecular basis for SSc pathogenesis in a well-studied mouse model of scleroderma. We profiled the skin and lung transcriptomes of mice at multiple timepoints, analysing the differential gene expression that underscores the development and resolution of bleomycin-induced fibrosis. RESULTS: We observed shared expression signatures of upregulation and downregulation in fibrotic skin and lung tissue, and observed significant upregulation of key pro-fibrotic genes including GDF15, Saa3, Cxcl10, Spp1 and Timp1. To identify changes in gene expression in responses to anti-fibrotic therapy, we assessed the effect of TGF-ß pathway inhibition via oral ALK5 (TGF-ß receptor I) inhibitor SB525334 and observed a time-lagged response in the lung relative to skin. We also implemented a machine learning algorithm that showed promise at predicting lung function using transcriptome data from both skin and lung biopsies. CONCLUSION: This study provides the most comprehensive look at the gene expression dynamics of an animal model of SSc to date, provides a rich dataset for future comparative fibrotic disease research, and helps refine our understanding of pathways at work during SSc pathogenesis and intervention.


Assuntos
Bleomicina , Escleroderma Sistêmico , Animais , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibrose , Perfilação da Expressão Gênica , Humanos , Pulmão/patologia , Camundongos , Escleroderma Sistêmico/induzido quimicamente , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Pele/patologia
6.
J Med Chem ; 64(19): 14773-14792, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34613725

RESUMO

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism. After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Doenças Metabólicas/tratamento farmacológico , N-Acetilglucosaminiltransferases/antagonistas & inibidores , Animais , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Humanos , Relação Estrutura-Atividade
7.
J Med Chem ; 64(21): 15549-15581, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34709814

RESUMO

The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).


Assuntos
Descoberta de Drogas , Fibrose Pulmonar/tratamento farmacológico , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Masculino , Camundongos , Estrutura Molecular , Fibrose Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Ácidos Lisofosfatídicos/metabolismo , Relação Estrutura-Atividade
8.
ACS Med Chem Lett ; 12(9): 1413-1420, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34531950

RESUMO

Herein we report the discovery and preclinical biological evaluation of 6-(2-(5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)-7-azaspiro[3.5]non-1-en-7-yl)-4-(trifluoromethyl)quinoline-2-carboxylic acid, compound 1 (BMS-986318), a nonbile acid farnesoid X receptor (FXR) agonist. Compound 1 exhibits potent in vitro and in vivo activation of FXR, has a suitable ADME profile, and demonstrates efficacy in the mouse bile duct ligation model of liver cholestasis and fibrosis. The overall profile of compound 1 supports its continued evaluation.

9.
Mucosal Immunol ; 12(1): 212-222, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30315241

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease, with unknown etiopathogenesis and suboptimal therapeutic options. Previous reports have shown that increased T-cell numbers and CD28null phenotype is predictive of prognosis in IPF, suggesting that these cells might have a role in this disease. Flow cytometric analysis of explanted lung cellular suspensions showed a significant increase in CD8+ CD28null T cells in IPF relative to normal lung explants. Transcriptomic analysis of CD3+ T cells isolated from IPF lung explants revealed a loss of CD28-transcript expression and elevation of pro-inflammatory cytokine expression in IPF relative to normal T cells. IPF lung explant-derived T cells (enriched with CD28null T cells), but not normal donor lung CD28+ T cells induced dexamethasone-resistant lung remodeling in humanized NSG mice. Finally, CD28null T cells expressed similar CTLA4 and significantly higher levels of PD-1 proteins relative to CD28+ T cells and blockade of either proteins in humanized NSG mice, using anti-CTLA4, or anti-PD1, mAb treatment-accelerated lung fibrosis. Together, these results demonstrate that IPF CD28null T cells may promote lung fibrosis but the immune checkpoint proteins, CTLA-4 and PD-1, appears to limit this effect.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/metabolismo , Fibrose Pulmonar Idiopática/imunologia , Pulmão/patologia , Receptor de Morte Celular Programada 1/metabolismo , Subpopulações de Linfócitos T/imunologia , Remodelação das Vias Aéreas , Animais , Anticorpos Monoclonais/metabolismo , Antígenos CD28/metabolismo , Antígeno CTLA-4/imunologia , Separação Celular , Células Cultivadas , Citometria de Fluxo , Humanos , Imunofenotipagem , Camundongos , Camundongos SCID , Receptor de Morte Celular Programada 1/imunologia
10.
J Med Chem ; 60(14): 6166-6190, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28635286

RESUMO

Agonism of the 5-HT2C receptor represents one of the most well-studied and clinically proven mechanisms for pharmacological weight reduction. Selectivity over the closely related 5-HT2A and 5-HT2B receptors is critical as their activation has been shown to lead to undesirable side effects and major safety concerns. In this communication, we report the development of a new screening paradigm that utilizes an active site mutant D134A (D3.32) 5-HT2C receptor to identify atypical agonist structures. We additionally report the discovery and optimization of a novel class of nonbasic heterocyclic amide agonists of 5-HT2C. SAR investigations around the screening hits provided a diverse set of potent agonists at 5-HT2C with high selectivity over the related 5-HT2A and 5-HT2B receptor subtypes. Further optimization through replacement of the amide with a variety of five- and six-membered heterocycles led to the identification of 6-(1-ethyl-3-(quinolin-8-yl)-1H-pyrazol-5-yl)pyridazin-3-amine (69). Oral administration of 69 to rats reduced food intake in an ad libitum feeding model, which could be completely reversed by a selective 5-HT2C antagonist.


Assuntos
Arginina/análogos & derivados , Flavonas/química , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Arginina/síntese química , Arginina/química , Arginina/farmacologia , Encéfalo/metabolismo , Células CACO-2 , Permeabilidade da Membrana Celular , Comportamento Alimentar/efeitos dos fármacos , Flavonas/síntese química , Flavonas/farmacologia , Células HEK293 , Humanos , Masculino , Membranas Artificiais , Camundongos Knockout , Microssomos Hepáticos/metabolismo , Mutação , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2B de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/genética , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinética , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Relação Estrutura-Atividade
11.
J Med Chem ; 59(19): 8848-8858, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27564419

RESUMO

The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.


Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Obesidade/tratamento farmacológico , Pirimidinas/química , Pirimidinas/uso terapêutico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Cães , Halogenação , Humanos , Macaca fascicularis , Masculino , Camundongos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 25(20): 4412-8, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26386604

RESUMO

Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible.


Assuntos
Encéfalo/efeitos dos fármacos , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Triazinas/farmacologia , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Obesidade/metabolismo , Ratos , Relação Estrutura-Atividade , Triazinas/administração & dosagem , Triazinas/química
13.
Bioorg Med Chem Lett ; 25(14): 2793-9, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26022839

RESUMO

Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.


Assuntos
Fármacos Antiobesidade/química , Pirazóis/química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Meia-Vida , Humanos , Obesidade/tratamento farmacológico , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Redução de Peso/efeitos dos fármacos
14.
J Med Chem ; 57(18): 7509-22, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25165888

RESUMO

Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).


Assuntos
Fármacos Antiobesidade/farmacologia , Descoberta de Drogas , Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/uso terapêutico , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Masculino , Ratos
15.
J Med Chem ; 56(23): 9586-600, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24182233

RESUMO

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.


Assuntos
Piridazinas/farmacocinética , Receptor CB1 de Canabinoide/antagonistas & inibidores , Triazóis/farmacocinética , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Descoberta de Drogas , Meia-Vida , Ligação Proteica , Piridazinas/química , Ratos , Relação Estrutura-Atividade , Triazóis/química
16.
Appetite ; 71: 466-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23624294

RESUMO

The adiposity hormone leptin has been implicated in the regulation of behavioral and metabolic controls of body weight. Leptin receptors are found in multiple peripheral and central tissues, particularly within hypothalamic and brainstem neuronal populations. Central leptinergic signaling acts as an indirect control to modulate the feeding inhibitory potency of the direct controls of meal size. Mouse models of neuronal leptin loss and gain of function have helped to identify and characterize how central leptin contributes to the central control of food intake.


Assuntos
Refeições , Tamanho da Porção , Receptores para Leptina/metabolismo , Adiposidade/fisiologia , Animais , Peso Corporal , Ingestão de Alimentos/fisiologia , Comportamento Alimentar , Humanos , Hipotálamo/metabolismo , Leptina/metabolismo , Modelos Animais , Obesidade/metabolismo , Transdução de Sinais
17.
Anal Bioanal Chem ; 397(7): 3137-42, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20549491

RESUMO

The formation of malonyl-CoA is catalyzed by acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of de novo fatty acid synthesis. Monitoring the changes of malonyl-CoA concentration in the brain in response to treatments such as pharmaceutical intervention (via ACC inhibitors) or different dietary conditions (such as varied feeding regimes) is of great interest and could help increase the understanding of how this molecule contributes to feeding behavior and overall energy balance. We have developed a sensitive analytical method for the determination of malonyl-CoA levels in rat brain tissue. The assay involved removal of tissue lipids by liquid-liquid extraction followed by LC/MS/MS analysis of the aqueous layer for malonyl-CoA. The method was sensitive enough (limit of quantitation = 50 ng/mL, or approximately 0.018 nmol/g brain tissue) to determine malonyl-CoA in individual rat brain preparations. The assay performance was sufficiently rugged to support drug discovery screening efforts and provided an additional analytical tool for monitoring brain malonyl-CoA levels.


Assuntos
Química Encefálica , Fracionamento Químico/métodos , Cromatografia Líquida/métodos , Malonil Coenzima A/análise , Espectrometria de Massas em Tandem/métodos , Animais , Malonil Coenzima A/isolamento & purificação , Ratos
18.
J Biol Chem ; 283(44): 29802-11, 2008 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-18768481

RESUMO

Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of the four intestinal membrane bound acyltransferases implicated in dietary fat absorption. Recently, it was found that, in addition to acylating diacylglycerol (DAG), DGAT1 also possesses robust enzymatic activity for acylating monoacylglycerol (MAG) (Yen, C. L., Monetti, M., Burri, B. J., and Farese, R. V., Jr. (2005) J. Lipid Res. 46, 1502-1511). In the current paper, we have conducted a detailed characterization of this reaction in test tube, intact cell culture, and animal models. Enzymatically, we found that triacylglycerol (TAG) synthesis from MAG by DGAT1 does not behave according to classic Michaelis-Menten kinetics. At low concentrations of 2-MAG (<50 microm), the major acylation product by DGAT1 was TAG; however, increased concentrations of 2-MAG (50-200 microm) resulted in decreased TAG formation. This unique product/substrate relationship is similar to MGAT3 but distinct from DGAT2 and MGAT2. We have also found that XP620 is an inhibitor that selectively inhibits the acylation of MAG by DGAT1 (IC(50) of human DGAT1: 16.6+/-4.0 nM (MAG as substrate) and 1499+/-318 nM (DAG as substrate); IC(50) values of human DGAT2, MGAT2, and MGAT3 are >30,000 nM). Using this pharmacological tool, we have shown that approximately 76 and approximately 89% of the in vitro TAG synthesis initiated from MAG is mediated by DGAT1 in Caco-2 cell and rat intestinal mucosal membranes, respectively. When applied to intact cultured cells, XP620 substantially decreased but did not abolish apoB secretion in differentiated Caco-2 cells. It also decreased TAG and DAG syntheses in primary enterocytes. Last, when delivered orally to rats, XP620 decreased absorption of orally administered lipids by approximately 50%. Based on these data, we conclude that the acylation of acylglycerols by DGAT1 is important for dietary fat absorption in the intestine.


Assuntos
Diacilglicerol O-Aciltransferase/biossíntese , Gorduras/metabolismo , Regulação da Expressão Gênica , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Administração Oral , Animais , Células CACO-2 , Diacilglicerol O-Aciltransferase/fisiologia , Gorduras na Dieta , Enterócitos/metabolismo , Compostos Heterocíclicos com 1 Anel , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley
20.
J Clin Invest ; 117(9): 2621-37, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17717599

RESUMO

Excess caloric intake can lead to insulin resistance. The underlying reasons are complex but likely related to ectopic lipid deposition in nonadipose tissue. We hypothesized that the inability to appropriately expand subcutaneous adipose tissue may be an underlying reason for insulin resistance and beta cell failure. Mice lacking leptin while overexpressing adiponectin showed normalized glucose and insulin levels and dramatically improved glucose as well as positively affected serum triglyceride levels. Therefore, modestly increasing the levels of circulating full-length adiponectin completely rescued the diabetic phenotype in ob/ob mice. They displayed increased expression of PPARgamma target genes and a reduction in macrophage infiltration in adipose tissue and systemic inflammation. As a result, the transgenic mice were morbidly obese, with significantly higher levels of adipose tissue than their ob/ob littermates, leading to an interesting dichotomy of increased fat mass associated with improvement in insulin sensitivity. Based on these data, we propose that adiponectin acts as a peripheral "starvation" signal promoting the storage of triglycerides preferentially in adipose tissue. As a consequence, reduced triglyceride levels in the liver and muscle convey improved systemic insulin sensitivity. These mice therefore represent what we believe is a novel model of morbid obesity associated with an improved metabolic profile.


Assuntos
Tecido Adiposo/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/anatomia & histologia , Tecido Adiposo/efeitos dos fármacos , Ração Animal , Animais , Diglicerídeos/metabolismo , Gorduras/farmacologia , Regulação da Expressão Gênica , Imuno-Histoquímica , Insulina/metabolismo , Resistência à Insulina/fisiologia , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Leptina/metabolismo , Lipoproteínas/metabolismo , Fígado/metabolismo , Macrófagos , Camundongos , Camundongos Transgênicos , Obesidade/induzido quimicamente , Tamanho do Órgão , PPAR gama/agonistas , PPAR gama/metabolismo , Fenótipo , Triglicerídeos/metabolismo
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