RESUMO
Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly efficacious orally active modulators of CB1R.
Assuntos
Naftiridinas/química , Piridinas/química , Receptor CB1 de Canabinoide/agonistas , Redução de Peso/efeitos dos fármacos , Administração Oral , Animais , Ingestão de Alimentos , Humanos , Naftiridinas/síntese química , Naftiridinas/farmacologia , Farmacocinética , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure-activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.
Assuntos
Fármacos Antiobesidade/síntese química , Piranos/síntese química , Piridinas/síntese química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Ligação Competitiva , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Cricetinae , Cricetulus , Cristalografia por Raios X , Cães , Agonismo Inverso de Drogas , Ingestão de Alimentos/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Glucuronídeos/metabolismo , Haplorrinos , Hepatócitos/metabolismo , Humanos , Camundongos , Camundongos Knockout , Modelos Moleculares , Conformação Molecular , Piranos/farmacocinética , Piranos/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Receptor CB1 de Canabinoide/genética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic, and metabolic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Assuntos
Desenho de Fármacos , Furanos/síntese química , Piridinas/síntese química , Receptor CB1 de Canabinoide/agonistas , Animais , Benzopiranos , Cães , Furanos/química , Furanos/farmacologia , Haplorrinos , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Knockout , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Ratos , Receptor CB1 de Canabinoide/genética , Relação Estrutura-AtividadeRESUMO
Selective inhibitors of biogenic amine (e.g., serotonin, norepinephrine, and dopamine) uptake exhibit varying degrees of safety and efficacy as antiobesity agents. Moreover, preclinical findings suggest that the combined inhibition of monoamine neurotransmitter transporters synergistically enhances antiobesity activity. (1R,5S)-(+)-1-(3,4-Dichlorophenyl)-3-azabicyclo-[3.1.0] hexane hydrochloride (DOV 21947) inhibits norepinephrine, 5-hydroxytryptamine, and dopamine uptake, and it reduces body weight in rodent models of diet-induced obesity (DIO). DIO rats treated orally with DOV 21947 for 1 to 24 days showed significantly lower body weights than vehicle-treated DIO rats. The decrease in body weight resulted specifically from a loss of retroperitoneal and mesenteric depots of white adipose tissue. DOV 21947 also reduced daily food intake in DIO rats, but consumption returned to control levels after 11 days of treatment. With the exception of a decrease in triglyceride levels, blood chemistry was unaltered after 24 days of DOV 21947 treatments. DOV 21947 had no effect on motor activity. Although DOV 21947 increased respiratory rate and decreased the tidal volume of normal rats, it did not alter the minute volume. In addition, DOV 21947 did not significantly affect blood pressure, heart rate, electrocardiographic indices or body temperature in telemeterized dogs. However, it caused a sustained, but reversible reduction in the rate of body weight gain for as long as 6 months in normal rats, and for up to 1 year in normal dogs. In summary, DOV 21947 is effective in causing a sustained and selective reduction in fat content and triglyceride levels in animal models of obesity without significantly altering vital organ function.
Assuntos
Compostos Aza/uso terapêutico , Peso Corporal/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Gorduras na Dieta/sangue , Modelos Animais de Doenças , Obesidade/tratamento farmacológico , Triglicerídeos/sangue , Animais , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Compostos Aza/farmacologia , Peso Corporal/fisiologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Gorduras na Dieta/efeitos adversos , Cães , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores da Captação de Neurotransmissores/farmacologia , Inibidores da Captação de Neurotransmissores/uso terapêutico , Obesidade/sangue , Ratos , Ratos Sprague-Dawley , Aumento de Peso/efeitos dos fármacos , Aumento de Peso/fisiologiaRESUMO
We document in vitro and in vivo effects of a novel, selective cannabinoid CB(1) receptor inverse agonist, Imidazole 24b (5-(4-chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)-1-methyl-imidazole-2-carboxamide). The in vitro binding affinity of Imidazole 24b for recombinant human and rat CB(1) receptor is 4 and 10 nM, respectively. Imidazole 24b binds to human cannabinoid CB(2) receptor with an affinity of 297 nM; in vitro, it is a receptor inverse agonist at both cannabinoid CB(1) and CB(2) receptors as it causes a further increase of forskolin-induced cAMP increase. Oral administration of Imidazole 24b blocked CP-55940-induced hypothermia, demonstrating cannabinoid CB(1) receptor antagonist efficacy in vivo. Using ex vivo autoradiography, Imidazole 24b resulted in dose-dependent increases in brain cannabinoid CB(1) receptor occupancy (RO) at 2h post-dosing in rats, indicating that approximately 50% receptor occupancy is sufficient for attenuation of receptor agonist-induced hypothermia. Imidazole 24b administered to C57Bl/6 mice and to dietary-induced obese (DIO) Sprague-Dawley rats attenuated overnight food intake with a minimal effective dose of 10 mg/kg, p.o. Administration had no effect in cannabinoid CB(1) receptor-deficient mice. DIO rats were dosed orally with vehicle, Imidazole 24b (1, 3 or 10 mg/kg), or dexfenfluramine (3 mg/kg) for 2 weeks. At 3 mg/kg, Imidazole 24b reduced cumulative food intake, leading to a non-significant decrease in weight gain. Imidazole 24b at 10 mg/kg and dexfenfluramine treatment inhibited food intake and attenuated weight gain. These findings suggest that selective cannabinoid CB(1) receptor inverse agonists such as Imidazole 24b have potential for the treatment of obesity.
Assuntos
Fármacos Antiobesidade/farmacologia , Imidazóis/farmacologia , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Administração Oral , Animais , Autorradiografia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dexfenfluramina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Agonismo Inverso de Drogas , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Imidazóis/administração & dosagem , Técnicas In Vitro , Masculino , Camundongos , Camundongos Knockout , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/agonistasRESUMO
The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364) and determined the relationship between efficacy and brain CB1R occupancy in rodents. MK-0364 was shown to be a highly potent CB1R inverse agonist that inhibited the binding and functional activity of various agonists with a binding K(i) of 0.13 nM for the human CB1R in vitro. MK-0364 dose-dependently inhibited food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats. CB1R mechanism-based effect was demonstrated for MK-0364 by its lack of efficacy in CB1R-deficient mice. Chronic treatment of DIO rats with MK-0364 dose-dependently led to significant weight loss with a minimum effective dose of 0.3 mg/kg (p.o.), or a plasma C(max) of 87 nM. Weight loss was accompanied by the loss of fat mass. Partial occupancy (30-40%) of brain CB1R by MK-0364 was sufficient to reduce body weight. The magnitude of weight loss was correlated with brain CB1R occupancy. The partial receptor occupancy requirement for efficacy was also consistent with the reduced food intake of the heterozygous mice carrying one disrupted allele of CB1R gene compared with the wild-type mice. These studies demonstrated that MK-0364 is a highly potent and selective CB1R inverse agonist and that it is orally active in rodent models of obesity.
Assuntos
Amidas/farmacologia , Fármacos Antiobesidade/farmacologia , Obesidade/tratamento farmacológico , Piridinas/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Amidas/química , Amidas/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/metabolismo , Ligação Competitiva/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Células CHO , Colforsina/farmacologia , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Cicloexanóis/farmacologia , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Indóis/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estrutura Molecular , Obesidade/metabolismo , Obesidade/fisiopatologia , Piperidinas/metabolismo , Piridinas/química , Piridinas/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/fisiologia , TransfecçãoRESUMO
Sulfonamide analogues of the potent CB1R inverse agonist taranabant were prepared and optimized for potency and selectivity for CB1R. They were variably more potent than the corresponding amide analogues. The most potent representative 22 had good pharmacokinetic and brain levels, but was modestly active in blocking CB1R agonist-mediated hypothermia.
Assuntos
Moduladores de Receptores de Canabinoides/síntese química , Receptor CB1 de Canabinoide/efeitos dos fármacos , Sulfonamidas/síntese química , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Química Encefálica , Moduladores de Receptores de Canabinoides/farmacologia , Humanos , Hipotermia/tratamento farmacológico , Concentração Inibidora 50 , Farmacocinética , Ratos , Receptor CB1 de Canabinoide/agonistas , Relação Estrutura-Atividade , Sulfonamidas/farmacologiaRESUMO
Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1.
Assuntos
Química Farmacêutica/métodos , Piridinas/química , Piridinas/síntese química , Receptor CB1 de Canabinoide/agonistas , Animais , Comportamento Animal/efeitos dos fármacos , Desenho de Fármacos , Comportamento Alimentar/efeitos dos fármacos , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Temperatura , Tolueno/químicaRESUMO
The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity.
Assuntos
Fármacos Antiobesidade/farmacologia , Canabinoides/farmacologia , Obesidade/tratamento farmacológico , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Peso Corporal/efeitos dos fármacos , Canabinoides/síntese química , Canabinoides/química , AMP Cíclico/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Ratos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismoRESUMO
Synthesis, SAR, and binding affinities are described for a new class of 1,8-naphthyridinone CB1 receptor specific inverse agonists. Food intake, knockout mouse, and pharmacokinetic evaluation of 14 indicate that this compound is an effective orally active modulator of CB1.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Administração Oral , Animais , Sítios de Ligação , Camundongos , Camundongos Knockout , Modelos Químicos , Naftiridinas/síntese química , Receptor CB1 de Canabinoide/agonistasRESUMO
Ghrelin, an acylated peptide secreted from the stomach, acts as a short-term signal of nutrient depletion. Ghrelin is an endogenous ligand for the GH secretagogue receptor 1a, a G protein-coupled receptor expressed in the hypothalamus and pituitary. We used a synthetic oligonucleotide, NOX-B11-2, capable of specific high-affinity binding to bioactive ghrelin to determine whether ghrelin neutralization would alter indices of energy balance in vivo. This novel type of ghrelin-blocking agent, called an RNA Spiegelmer (SPM), is a polyethylene glycol-modified l-RNA oligonucleotide, the nonnatural configuration of which confers in vivo stability. NOX-B11-2 blocked ghrelin mediated activation of GH secretagogue receptor 1a in cell culture (IC50 approximately 5 nm). We explored the effects of acute NOX-B11-2 administration on ghrelin-induced feeding in mice. NOX-B11-2 (66 mg/kg, sc) blocked ghrelin-induced feeding and was without effect on feeding evoked by an orally active nonpeptide ghrelin receptor agonist. We demonstrated that selective ghrelin blockade effectively promoted weight loss in diet-induced obese (DIO) mice. Chronic infusion of NOX-B11-2 (33 mg/kg.d, sc) to DIO mice evoked body weight loss for 13 d and reduced food intake and fat mass relative to control SPM-infused mice. In a 7-d study, DIO mice infused with NOX-B11-2 (33 mg/kg.d, sc) showed body weight loss, compared with animals receiving control SPM. This effect was directly mediated by SPM neutralization of ghrelin because NOX-B11-2 administration to ghrelin-deficient mice resulted in no weight loss. The decreased obesity observed in SPM-treated DIO mice provides validation for ghrelin neutralization as a potential antiobesity therapy.
Assuntos
Oligonucleotídeos/farmacologia , Hormônios Peptídicos/metabolismo , Animais , Fármacos Antiobesidade/farmacologia , Comportamento Animal , Peso Corporal , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Comportamento Alimentar , Genes Reporter , Grelina , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Fatores de Transcrição NFATC/metabolismo , Obesidade , Oligonucleotídeos/química , Hormônios Peptídicos/química , Peptídeos/química , Polietilenoglicóis/química , Ligação Proteica , RNA/química , Radioimunoensaio , Fatores de Tempo , beta-Lactamases/metabolismoRESUMO
Structure-activity relationship studies directed toward the optimization of 4,5-diarylimidazole-2-carboxamide analogs as human CB1 receptor inverse agonists resulted in the discovery of the two amide derivatives 24a and b (hCB1 IC50 = 6.1 and 4.0 nM) which also demonstrated efficacy in overnight feeding studies in the rat for reduction in both food intake and overall body weight.