RESUMO
The syntheses and SAR investigations of novel CB(1) receptor antagonists based on a 1,2-diaryl piperidine core have been described. Optimization of this core afforded a compound with robust in vivo potency by reducing food intake in a mouse DIO model.
Assuntos
Piperidinas/química , Piperidinas/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Dieta/efeitos adversos , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Camundongos , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismo , Piperidinas/administração & dosagem , Ligação Proteica/fisiologia , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
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/farmacologiaRESUMO
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/farmacologiaRESUMO
Melanin concentrating hormone (MCH) is involved in regulation of food intake and energy homeostasis. Antagonists of the MCH receptor are expected to affect food intake and weight gain, making MCH-R1 an attractive target for obesity treatment. Herein, we report the discovery of a novel, orally active series of MCH-R1 antagonists that exhibit in vivo efficacy in rodent obesity models.
Assuntos
Fármacos Antiobesidade/síntese química , Compostos Bicíclicos com Pontes/síntese química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Disponibilidade Biológica , Encéfalo/metabolismo , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Cicloeptanos/síntese química , Cicloeptanos/química , Cicloeptanos/farmacologia , Cicloexanos/síntese química , Cicloexanos/química , Cicloexanos/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Camundongos , Obesidade/tratamento farmacológico , Ratos , Ureia/química , Ureia/farmacologiaRESUMO
Herein, we report a small molecule MCH-R1 antagonist which demonstrates oral efficacy in chronic rodent models. Substituted phenyl biaryl urea derivatives were synthesized and evaluated as MCH-R1 antagonists for the treatment of obesity. The structure-activity relationship studies in this series resulted in identification of urea 1 as a potent and selective MCH-R1 antagonist. Compound 1 exhibited oral efficacy in chronic (28 d) rodent models at 3-30 mpk showing significant reduction in food intake and weight gain relative to controls.
Assuntos
Obesidade/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Cálcio/metabolismo , Células Cultivadas , Doença Crônica , Humanos , Obesidade/metabolismo , Ratos , Receptores de Somatostatina/genética , Relação Estrutura-Atividade , Ureia/farmacologiaRESUMO
Prior work has demonstrated that melanin-concentrating hormone-1 (MCH-1) receptor antagonism decreases food intake and body weight in obese rodents. The purpose of this study was to determine if the MCH-1 receptor antagonist-mediated hypophagia was due a decrease in meal size, meal frequency, or both. We performed a meal pattern analysis in free-feeding hyperphagic diet-induced obese (DIO) rats treated with 1, 3 or 10 mg/kg p.o. of the MCH-1 receptor antagonist T-226296 (a (-)enantiomer of N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4'-fluoro[1,1'-biphenyl]-4 carboxamide). Food intake was continuously monitored for 24 h using a BioDAQ food intake monitoring system. A total of 10 mg/kg T-226296 significantly decreased body weight and 24-h food intake, and had no effect on locomotor activity. The decrease in food intake was due to a reduction in meal size, not meal frequency. We conclude that MCH-1 receptor antagonism with T-226296 decreases food intake in DIO rats by selectively reducing meal size, and that the reduced food intake is not due to a generalized behavioral malaise.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Atividade Motora/efeitos dos fármacos , Naftalenos/administração & dosagem , Naftalenos/química , Naftalenos/farmacologia , Obesidade/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Fatores de TempoRESUMO
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 farmacológicoRESUMO
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 ERGRESUMO
A series of novel aminobenzimidazoles was prepared and evaluated for h-MCH-R1 antagonist properties. Most of the compounds showed excellent h-MCH-R1 binding affinity as well as mouse ex vivo binding. Compounds 9 and 18 were active in mouse DIO studies at 30mpk.
Assuntos
Fármacos Antiobesidade/farmacologia , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Doenças Metabólicas/tratamento farmacológico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/química , Benzimidazóis/química , Ligação Competitiva/efeitos dos fármacos , Dieta , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Obesos , Conformação Molecular , Obesidade/tratamento farmacológico , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Melanin concentrating hormone (MCH) receptor antagonists have been proposed as potential treatments of obesity. MCH receptor antagonists with a biphenylamine subunit have been reported previously at Schering-Plough. Herein, we report the discovery of bicyclo[4.1.0]heptanes as replacements for the middle phenyl ring of the biphenylamine moiety in order to eliminate its potential mutagenic liability. Structure-activity relationships in this series were found to be very similar to those of the original biphenylamine series, suggesting that the two series have similar binding modes.
Assuntos
Compostos de Aminobifenil/química , Compostos Bicíclicos com Pontes/química , Heptanos/química , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Animais , Linhagem Celular , Cricetinae , Avaliação Pré-Clínica de Medicamentos , Heptanos/farmacologia , Camundongos , Estrutura Molecular , Mutagênicos/química , Ratos , Relação Estrutura-AtividadeRESUMO
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-AtividadeRESUMO
OBJECTIVE: To characterize the meal patterns of free feeding Sprague-Dawley rats that become obese or resist obesity when chronically fed a high-fat diet. RESEARCH METHODS AND PROCEDURES: Male Sprague-Dawley rats (N = 120) were weaned onto a high-fat diet, and body weight was monitored for 19 weeks. Rats from the upper [diet-induced obese (DIO)] and lower [diet-resistant (DR)] deciles for body-weight gain were selected for study. A cohort of chow-fed (CF) rats weight-matched to the DR group was also studied. Food intake was continuously monitored for 7 consecutive days using a BioDAQ food intake monitoring system. RESULTS: DIO rats were obese, hyperphagic, hyperleptinemic, hyperinsulinemic, hyperglycemic, and hypertriglyceridemic relative to the DR and CF rats. The hyperphagia of DIOs was caused by an increase in meal size, not number. CF rats ate more calories than DR rats; however, this was because of an increase in meal number, not size. When expressed as a function of lean mass, CF and DR rats consumed the same amount of calories. The intermeal intervals of DIO and DR rats were similar; both were longer than CF rats. The nocturnal satiety ratio of DIO rats was significantly lower than DR and CF rats. The proportion of calories eaten during the nocturnal period did not differ among groups. DISCUSSION: The hyperphagia of a Sprague-Dawley rat model of chronic diet-induced obesity is caused by an increase in meal size, not number. These results are an important step toward understanding the mechanisms underlying differences in feeding behavior of DIO and DR rats.
Assuntos
Dieta , Alimentos , Predisposição Genética para Doença , Obesidade/etiologia , Obesidade/genética , Animais , Composição Corporal , Ritmo Circadiano , Ingestão de Alimentos , Ingestão de Energia , Hiperglicemia/etiologia , Hiperinsulinismo/etiologia , Hiperfagia , Hipertrigliceridemia/etiologia , Insulina/sangue , Leptina/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Saciação , Aumento de PesoRESUMO
By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings: (i) a highly selective non-peptide MC4R agonist augments erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type but not Mc4r-null mice; (ii) copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r; (iii) reverse transcription (RT)-PCR and non-PCR based methods demonstrate MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and (iv) in situ hybridization of glans tissue from the human and rat penis reveal MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. Our results provide a basis for the existence of MC4R-controlled neuronal pathways that control sexual function.