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1.
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
2.
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
3.
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
4.
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
5.
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 , Perda de Peso/efeitos dos fármacos
6.
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
7.
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
8.
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
9.
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
10.
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
12.
Physiol Behav ; 82(1): 81-7, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15234595

RESUMO

Gerry Smith's emphasis on the meal as the functional unit of ingestion spurred experiments designed to (1) identify oral and postoral stimuli that affect meal size, and (2) identify peripheral and central neural mechanisms involved in the processing of sensory signals generated by these stimuli. His observations that gut-brain peptides can limit meal size were important in formulating the idea that neuropeptides involved in the control of food intake modulate the peripheral and central neural processing of meal-stimulated sensory signals. This focus on meal size continues to foster the development of hypotheses and the design of experiments that characterize the sites and modes of action of feeding modulatory neuropeptides. These investigations have focused attention on the gut-brain neuraxis as a critical sensory pathway in the control of ingestive behavior, and have revealed important integrative properties of peripheral and central neurons along this axis. The neuromodulatory function of peptides that alter food intake is supported by their ability to recruit the activation of neurons at multiple central nodes of the gut-brain axis and to affect the neural processing and behavioral potency of meal-related gastrointestinal signals important in the negative feedback control of meal size. This sensory neurobiological perspective may also be applied to determine whether feeding modulatory neuropeptides affect the neural and behavioral potency of oral positive feedback signals that promote ingestion.


Assuntos
Comportamento Alimentar/fisiologia , Neuropeptídeos/fisiologia , Células Receptoras Sensoriais/fisiologia , Transdução de Sinais/fisiologia , Hormônio Adrenocorticotrópico/fisiologia , Animais , Humanos , Leptina/fisiologia , Neurobiologia
13.
Appetite ; 42(1): 107-9, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15036789

RESUMO

Transgenic mice are a powerful and much used tool in the field of feeding behavior. However, much of the biobehavioral characterization of the controls of feeding has been done in rats. The present presentation describes our efforts to adapt techniques traditionally used in rats to the analysis of feeding behavior in mice. This has been done within Smith's theoretical framework of positive and negative feedback controls of meal size. We show that mice are sensitive to increases and decreases of post-ingestive negative feedback, as they reduce intake in response to intragastric nutrient preloads and CCK, while they increase their intake in a sham-feeding preparation. Finally, we discuss our initial attempts to characterize the controls of feeding in a transgenic mouse model, the NSE-RB mouse.


Assuntos
Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Camundongos Transgênicos , Animais , Colecistocinina/sangue , Fenômenos Fisiológicos do Sistema Digestório , Ingestão de Alimentos/genética , Retroalimentação/fisiologia , Camundongos , Modelos Animais , Ratos , Saciação
14.
Physiol Behav ; 77(2-3): 411-6, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12419417

RESUMO

Central melanocortin (MC) receptor agonists inhibit food intake and may be downstream mediators of the effects of central leptin, which (1) reduces food intake by selectively decreasing meal size and (2) augments the feeding-inhibitory effects of gastrointestinal food stimuli. Central administration of the MC-3/4 receptor (MC-3/4R) agonist, MTII, inhibits feeding in rats, but its effects on meal pattern and potential interactions with gastrointestinal controls of food intake remain unclear. We examined meal patterns and intake in male Sprague-Dawley rats following central intracerebroventricular administration of MTII (0.01-1.0 nmol) in two situations: (1) during daytime 60-min scheduled access to liquid glucose (12.5%) in combination with a duodenal preload of 12.5% glucose or physiological saline (4.4 ml/10 min), and (2) during subsequent overnight access to 45 mg of solid chow pellets. Both duodenal glucose preloads and MTII reduced subsequent glucose intake. However, no dose of MTII augmented the reductions in food intake produced by duodenal glucose alone. During overnight access to pelleted chow, the 0.1- and 1.0-nmol doses of MTII reduced food intake, meal size, meal duration, and body weight, and increased the satiety ratio (duration of intermeal interval/preceding meal size) but did not change meal frequency. The present data (1) demonstrate that MTII, like leptin, reduces food intake by a selective reduction in meal size and not meal frequency, and (2) suggest that MTII increases the feeding-inhibitory potency of negative feedback signals critical to the control of meal size during spontaneous chow access, but not scheduled access to palatable liquid nutrient solutions.


Assuntos
Duodeno/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Receptores da Corticotropina/agonistas , Animais , Peso Corporal/efeitos dos fármacos , Retroalimentação/fisiologia , Glucose/administração & dosagem , Glucose/farmacologia , Injeções Intraventriculares , Intubação Gastrointestinal , Masculino , Oligopeptídeos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores de Melanocortina , Resposta de Saciedade/efeitos dos fármacos , alfa-MSH/análogos & derivados
15.
Physiol Behav ; 77(1): 11-18, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12213497

RESUMO

Morphine (MOR) is known to inhibit maternal behavior and induce hyperthermia; at appropriate doses, concurrent administration of naloxone (NAL) counteracts its disruption of maternal behavior but not the hyperthermia. We used these findings to evaluate the view that lactating rats terminate nursing due to intolerable hyperthermia. After a dam-litter separation of 4 h on Day 7 postpartum (PP), mother-litter interactions were observed continuously for 1 h. One hour before reunion, the dams received two injections (1 ml/kg ip each) of saline (SAL), MOR (20 mg/kg) and/or NAL (1 mg/kg) in the following combinations (n = 7 each): SAL + SAL, SAL + NAL, MOR + SAL or MOR + NAL. MOR profoundly disrupted maternal behavior, thereby preventing litter weight gains; these effects were completely counteracted by NAL, which alone had no discernible effects. In contrast, MOR-induced hyperthermia (approximately 0.7 degrees C increase in each hour, before and after reunion with pups) was not antagonized by NAL at the doses used. Thus, an additional 0.7-1.4 degrees C of body temperature (T) did not delay the onset or reduce the duration of nursing compared with SAL-treated controls. Further, there were no group differences in behaviors displayed both shortly before and after a nursing bout that included milk ejections or in the resumption of nursing. Together with earlier methodological and empirical criticisms of the thermal control theory, as well as knowledge about the somatosensory determinants of nursing, the present results suggest that nursing bouts in lactating rats are not limited by the mother's T.


Assuntos
Febre/fisiopatologia , Lactação , Animais , Temperatura Corporal/efeitos dos fármacos , Combinação de Medicamentos , Feminino , Febre/induzido quimicamente , Injeções Intraperitoneais , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/farmacologia , Ratos , Ratos Long-Evans , Valores de Referência , Cloreto de Sódio/farmacologia
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