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1.
Biochim Biophys Acta Mol Basis Dis ; 1870(1): 166908, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37793464

RESUMO

Metabolic disorders such as type 2 diabetes, fatty liver disease, hyperlipidemia, and obesity commonly co-occur but clinical treatment options do not effectively target all disorders. Calorie restriction, semaglutide, rosiglitazone, and mitochondrial uncouplers have all demonstrated efficacy against one or more obesity-related metabolic disorders, but it currently remains unclear which therapeutic strategy best targets the combination of hyperglycaemia, liver fat, hypertriglyceridemia, and adiposity. Herein we performed a head-to-head comparison of 5 treatment interventions in the female db/db mouse model of severe metabolic disease. Treatments included ∼60 % calorie restriction (CR), semaglutide, rosiglitazone, BAM15, and niclosamide ethanolamine (NEN). Results showed that BAM15 and CR improved body weight and liver steatosis to levels superior to semaglutide, NEN, and rosiglitazone, while BAM15, semaglutide, and rosiglitazone improved glucose tolerance better than CR and NEN. BAM15, CR, semaglutide, and rosiglitazone all had efficacy against hypertriglyceridaemia. These data provide a comprehensive head-to-head comparison of several key treatment strategies for metabolic disease and highlight the efficacy of mitochondrial uncoupling to correct multiple facets of the metabolic disease milieu in female db/db mice.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Feminino , Niclosamida/uso terapêutico , Rosiglitazona/farmacologia , Rosiglitazona/uso terapêutico , Etanolamina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Restrição Calórica , Etanolaminas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo
2.
J Med Chem ; 66(6): 3876-3895, 2023 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-36882080

RESUMO

Small-molecule mitochondrial uncouplers are gaining recognition as potential therapeutics for metabolic diseases such as obesity, diabetes, and nonalcoholic steatohepatitis (NASH). Specifically, heterocycles derived from BAM15, a potent and mitochondria-selective uncoupler, have yielded promising preclinical candidates that are efficacious in animal models of obesity and NASH. In this study, we report the structure-activity relationship studies of 6-amino-[1,2,5]oxadiazolo[3,4-b]pyridin-5-ol derivatives. Using oxygen consumption rate as a readout of mitochondrial uncoupling, we established 5-hydroxyoxadiazolopyridines as mild uncouplers. In particular, SHM115, which contains a pentafluoro aniline, had an EC50 value of 17 µM and exhibited 75% oral bioavailability. SHM115 treatment increased the energy expenditure and lowered the body fat mass in two diet-induced obesity mouse models, including an obesity prevention model and an obesity reversal model. Taken together, our findings demonstrate the therapeutic potential of mild mitochondrial uncouplers for the prevention of diet-induced obesity.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Mitocôndrias/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Dieta , Consumo de Oxigênio
3.
Mol Metab ; 69: 101684, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36731653

RESUMO

OBJECTIVE: Calorie restriction is a first-line treatment for overweight individuals with metabolic impairments. However, few patients can adhere to long-term calorie restriction. An alternative approach to calorie restriction that also causes negative energy balance is mitochondrial uncoupling, which decreases the amount of energy that can be extracted from food. Herein we compare the metabolic effects of calorie restriction with the mitochondrial uncoupler BAM15 in the db/db mouse model of severe hyperglycemia, obesity, hypertriglyceridemia, and fatty liver. METHODS: Male db/db mice were treated with ∼50% calorie restriction, BAM15 at two doses of 0.1% and 0.2% (w/w) admixed in diet, or 0.2% BAM15 with time-restricted feeding from 5 weeks of age. Mice were metabolically phenotyped over 4 weeks with assessment of key readouts including body weight, glucose tolerance, and liver steatosis. At termination, liver tissues were analysed by metabolomics and qPCR. RESULTS: Calorie restriction and high-dose 0.2% BAM15 decreased body weight to a similar extent, but mice treated with BAM15 had far better improvement in glucose control. High-dose BAM15 treatment completely normalized fasting glucose and glucose tolerance to levels similar to lean db/+ control mice. Low-dose 0.1% BAM15 did not affect body mass but partially improved glucose tolerance to a similar degree as 50% calorie restriction. Both calorie restriction and high-dose BAM15 significantly improved hyperglucagonemia and liver and serum triglyceride levels. Combining high-dose BAM15 with time-restricted feeding to match the time that calorie restricted mice were fed resulted in the best metabolic phenotype most similar to lean db/+ controls. BAM15-mediated improvements in glucose control were associated with decreased glucagon levels and decreased expression of enzymes involved in hepatic gluconeogenesis. CONCLUSIONS: BAM15 and calorie restriction treatments improved most metabolic disease phenotypes in db/db mice. However, mice fed BAM15 had superior effects on glucose control compared to the calorie restricted group that consumed half as much food. Submaximal dosing with BAM15 demonstrated that its beneficial effects on glucose control are independent of weight loss. These data highlight the potential for mitochondrial uncoupler pharmacotherapies in the treatment of metabolic disease.


Assuntos
Fígado Gorduroso , Doenças Metabólicas , Masculino , Camundongos , Animais , Restrição Calórica , Glicemia/análise , Peso Corporal , Glucose , Camundongos Endogâmicos
4.
Org Lett ; 22(17): 7013-7018, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32846095

RESUMO

We report a transition-metal-free trans-selective semireduction of alkynes with pinacolborane and catalytic potassium tert-butoxide. A variety of 3-substituted primary and secondary propiolamides, including an analog of FK866, a potent nicotinamide mononucleotide adenyltransferase (NMNAT) inhibitor, are reduced to the corresponding (E)-3-substituted acrylamide derivatives in up to 99% yield with >99:1 E/Z selectivity. Mechanistic studies suggest that an activated Lewis acid-base complex transfers a hydride to the α-carbon followed by rapid protonation in a trans fashion.

5.
J Med Chem ; 63(11): 6203-6224, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32392051

RESUMO

Small molecule mitochondrial uncouplers have recently garnered great interest for their potential in treating nonalcoholic steatohepatitis (NASH). In this study, we report the structure-activity relationship profiling of a 6-amino[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol core, which utilizes the hydroxy moiety as the proton transporter across the mitochondrial inner membrane. We demonstrate that a wide array of substituents is tolerated with this novel scaffold that increased cellular metabolic rates in vitro using changes in oxygen consumption rate as a readout. In particular, compound SHS4121705 (12i) displayed an EC50 of 4.3 µM in L6 myoblast cells and excellent oral bioavailability and liver exposure in mice. In the STAM mouse model of NASH, administration of 12i at 25 mg kg-1 day-1 lowered liver triglyceride levels and improved liver markers such as alanine aminotransferase, NAFLD activity score, and fibrosis. Importantly, no changes in body temperature or food intake were observed. As potential treatment of NASH, mitochondrial uncouplers show promise for future development.


Assuntos
Pirazinas/química , Alanina Transaminase/metabolismo , Compostos de Anilina/química , Animais , Linhagem Celular , Dieta Hiperlipídica , Modelos Animais de Doenças , Meia-Vida , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Mitocôndrias/metabolismo , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Consumo de Oxigênio/efeitos dos fármacos , Pirazinas/farmacocinética , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Triglicerídeos/metabolismo , Proteína Desacopladora 1/química , Proteína Desacopladora 1/metabolismo
6.
Nat Commun ; 11(1): 2397, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409697

RESUMO

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.


Assuntos
Diaminas/administração & dosagem , Resistência à Insulina , Mitocôndrias/efeitos dos fármacos , Obesidade/tratamento farmacológico , Oxidiazóis/administração & dosagem , Pirazinas/administração & dosagem , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Administração Oral , Animais , Glicemia/análise , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Diaminas/efeitos adversos , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Técnica Clamp de Glucose , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Obesidade/sangue , Obesidade/etiologia , Obesidade/metabolismo , Oxidiazóis/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Pirazinas/efeitos adversos
7.
J Med Chem ; 63(5): 2511-2526, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32017849

RESUMO

Small molecule mitochondrial uncouplers are emerging as a new class of molecules for the treatment of nonalcoholic steatohepatitis. We utilized BAM15, a potent protonophore that uncouples the mitochondria without depolarizing the plasma membrane, as a lead compound for structure-activity profiling. Using oxygen consumption rate as an assay for determining uncoupling activity, changes on the 5- and 6-position of the oxadiazolopyrazine core were introduced. Our studies suggest that unsymmetrical aniline derivatives bearing electron withdrawing groups are preferred compared to the symmetrical counterparts. In addition, alkyl substituents are not tolerated, and the N-H proton of the aniline ring is responsible for the protonophore activity. In particular, compound 10b had an EC50 value of 190 nM in L6 myoblast cells. In an in vivo model of NASH, 10b decreased liver triglyceride levels and showed improvement in fibrosis, inflammation, and plasma ALT. Taken together, our studies indicate that mitochondrial uncouplers have potential for the treatment of NASH.


Assuntos
Diaminas/uso terapêutico , Mitocôndrias Hepáticas/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pirazinas/uso terapêutico , Desacopladores/uso terapêutico , Animais , Diaminas/química , Diaminas/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Oxidiazóis/química , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Consumo de Oxigênio/efeitos dos fármacos , Pirazinas/química , Pirazinas/farmacologia , Desacopladores/química , Desacopladores/farmacologia
8.
PLoS One ; 12(7): e0182495, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28759642

RESUMO

Folliculostellate cell gap junctions establish a network for the transmission of information within the anterior pituitary. Connexins make up gap junction channels. Changes in connexin (Cx) turnover modify gap junction-mediated intercellular communication. We have reported that cytokines and hormones influence Cx43 turnover and coupling in folliculostellate cells and in the folliculostellate cell line TtT/GF. In addition, the expression of different connexins alters intercellular communication and connexins may have functions besides cell coupling. Here we assessed the expression, turnover and subcellular localization of Cx46 and Cx50 in the anterior pituitary and TtT/GF cells. Then, we assessed the impact of various natural (lactation, annual reproductive cycle, bFGF) and pathological (autoimmune orchitis, diabetes/obesity) conditions associated with altered anterior pituitary hormone secretion on Cx46 and Cx50. Anterior pituitary Cx46 and Cx50 expression and subcellular distribution were cell-dependent. Cx46 was expressed by folliculostellate, TtT/GF and endocrine cells. In the cytoplasm, Cx46 was chiefly associated with lysosomes. Variously sized Cx46 molecules were recovered exclusively in the TtT/GF cell nuclear fraction. In the nucleus, Cx46 co-localized with Nopp-140, a nucleolar factor involved in rRNA processing. Neither cytoplasmic nor nuclear Cx46 and Cx43 co-localized. Cx50 localized to folliculostellate and TtT/GF cells, and to the walls of blood capillaries, not to endocrine cells. Cx50 was cytoplasmic and associated with the cell membrane, not nuclear. Cx50 did not co-localize with Cx46 but it co-localized in the cytoplasm and co-immunoprecipitated with Cx43. Cx46 and Cx50 responses to various physiological and pathological challenges were different, often opposite. Cx46 and Cx43 expression and phosphorylation profiles differed in the anterior pituitary, whereas Cx50 and Cx43 were similar. The data suggest that Cx46 participates to cellular growth and proliferation and that Cx50, together with Cx43, contributes to folliculostellate cell coupling.


Assuntos
Conexinas/metabolismo , Adeno-Hipófise/metabolismo , Animais , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Células Cultivadas , Conexinas/genética , Diabetes Mellitus/metabolismo , Células Endócrinas/metabolismo , Células Epiteliais/metabolismo , Feminino , Lactação/metabolismo , Lisossomos/metabolismo , Masculino , Camundongos , Vison , Obesidade/metabolismo , Orquite/metabolismo , Adeno-Hipófise/citologia , Hormônios Adeno-Hipofisários/metabolismo , Reprodução
9.
Histochem Cell Biol ; 136(3): 245-66, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21785947

RESUMO

Wild-type (WT) and myosin heavy chain IIB null [MHCIIB (-/-)] embryonic fibroblasts were used as an experimental model to assess the role of the isoform B of myosin II (MII) in the regulation of the cell shape and intrinsic polarity. Genetic ablation of MHCIIB causes a persistent albeit, unstable protrusive activity in embryonic fibroblasts (Lo et al. in Nonmuscle myosin IIB is involved in the guidance of fibroblast migration. Mol Biol Cell 15:982-989, 2004). Here, we show that MHCIIB-deficient fibroblasts are characterized by a sustained guanine nucleotide exchange factor (GEF)-dependent activation of the small GTPase Rac-1 that is responsible for the continual lamellipodium formation. Moreover, we observed a sustained PKC-ζ activation and an increased association of cortactin with the plasma membrane in the MHCIIB (-/-) cells that were also dependent on GEF-mediated Rac-1 activation. Rac-1 activation and its downstream effects were induced in WT fibroblasts by inhibiting MII ATPase and crosslinking activities, suggesting that an altered actin-MII interaction favours Rac-1 activation, regardless of the MII isoform implicated. In addition, we found MIIB isoform-specific effects that were independent of Rac-1 activation. MHCIIA interacts with cortactin whereas MHCIIB does not. By contrast, MHCIIB interacts with Lgl1, a member of the Scribble/Dlg/Lgl polarity complex, whereas MHCIIA does not. MHCIIB (-/-) fibroblasts exhibited deregulated endogenous levels of the Par polarity complex members, Par3 and Par6. Together, the data show that MHCIIB deficiency causes imbalances in signalling pathways that are responsible for cell polarity determination. The results suggest that these pathways are targets of MIIB in the regulation of the cell's shape and polarity.


Assuntos
Polaridade Celular/genética , Fibroblastos/metabolismo , Miosina não Muscular Tipo IIB/genética , Animais , Citosol/metabolismo , Fibroblastos/citologia , Reguladores de Proteínas de Ligação ao GTP/genética , Reguladores de Proteínas de Ligação ao GTP/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Transgênicos , Miosina não Muscular Tipo IIB/metabolismo , Fosforilação , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
10.
Org Biomol Chem ; 8(20): 4601-6, 2010 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-20725690

RESUMO

In high throughput screening (HTS) campaigns, the quality and cost of commercial reagents suitable for pilot studies often create obstacles upon scale-up to a full screen. We faced such challenges in our efforts to implement an HTS for inhibitors of the phosphopantetheinyl transferase Sfp using an assay that had been validated using commercially available reagents. Here we demonstrate a facile route to the synthetic preparation of reactive tetraethylrhodamine and quencher probes, and their application to economically produce fluorescent and quencher-modified substrates. These probes were prepared on a scale that would allow a full, quantitative HTS of more than 350,000 compounds.


Assuntos
Transferência Ressonante de Energia de Fluorescência , Corantes Fluorescentes/síntese química , Rodaminas/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Corantes Fluorescentes/química , Inibidores de Proteínas Quinases/química , Rodaminas/química , Transferases (Outros Grupos de Fosfato Substituídos)/antagonistas & inibidores
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