RESUMEN
A series of conformationally restricted acetanilides were synthesized and evaluated as ß3-adrenergic receptor agonists (ß3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine ß3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent ß3-AR mediated responses in a rat bladder hyperactivity model.
Asunto(s)
Acetanilidas/síntesis química , Acetanilidas/farmacología , Agonistas de Receptores Adrenérgicos beta 3/síntesis química , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Acetanilidas/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 3/uso terapéutico , Animales , Células CHO , Cricetinae , Cricetulus , Diseño de Fármacos , Humanos , Espectroscopía de Resonancia Magnética , Conformación MolecularRESUMEN
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.
Asunto(s)
Piperazinas/química , Receptor de Melanocortina Tipo 4/agonistas , Urea/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Haplorrinos , Ratones , Obesidad/tratamiento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/genética , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-Actividad , Urea/química , Urea/farmacocinética , Urea/uso terapéuticoRESUMEN
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.
Asunto(s)
Obesidad/tratamiento farmacológico , Receptor de Melanocortina Tipo 4/agonistas , Triazoles/farmacología , Animales , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Estructura Molecular , Ratas , Receptor de Melanocortina Tipo 4/genética , Relación Estructura-Actividad , Triazoles/química , Triazoles/uso terapéuticoRESUMEN
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Asunto(s)
Ligandos , Receptor de Melanocortina Tipo 4/agonistas , Animales , Humanos , Piperazina , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-ActividadRESUMEN
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
Asunto(s)
Amidas/química , Fármacos Antiobesidad/química , Obesidad/tratamiento farmacológico , Pirrolidinas/química , Receptor de Melanocortina Tipo 4/agonistas , Compuestos de Espiro/química , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/uso terapéutico , Peso Corporal/efectos de los fármacos , Humanos , Ratones , Ratones Noqueados , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/metabolismo , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/uso terapéutico , Relación Estructura-ActividadRESUMEN
Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed.
Asunto(s)
Piperidinas/química , Receptor de Melanocortina Tipo 4/agonistas , Administración Oral , Animales , Encéfalo/metabolismo , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Conformación Molecular , Piperidinas/síntesis química , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/metabolismo , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.
Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Indanos/química , Indanos/uso terapéutico , Receptor de Melanocortina Tipo 4/agonistas , Receptor de Melanocortina Tipo 4/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/uso terapéutico , Animales , Células CHO , Cricetinae , Cricetulus , Perros , Haplorrinos , Humanos , Indanos/farmacocinética , Indanos/farmacología , Masculino , Ratones , Estructura Molecular , Unión Proteica , Ratas , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
In this study we have characterized the anti-inflammatory profile of a selective melanocortin type 3 receptor (MC3-R) ligand [D-Trp8]-gamma-MSH, validating in vitro results with analyses in mice deficient for this receptor subtype. In wild-type (WT) macrophages, [D-Trp8]-gamma-MSH activated MC3-R (as tested by accumulation of cyclic AMP) and inhibited (approximately 50%) the release of interleukin (IL)-1 and the chemokine KC (CXCL1), but was ineffective in cells taken from MC3-R null mice. In vivo, administration of 3-30 microg [D-Trp8]-gamma-MSH significantly inhibited leukocyte influx and cytokine production in a model of crystal-induced peritonitis, and these effects were absent in MC3-R null mice or blocked by coadministration of an MC3-R antagonist. Finally, in a model of gouty arthritis, direct injection of urate crystals into the rat joint provoked a marked inflammatory reaction that was significantly inhibited (approximately 70%) by systemic or local administration of [D-Trp8]-gamma-MSH. In conclusion, using an integrated transgenic and pharmacological approach, we provide strong proof of concept for the development of selective MC3-R agonists as novel anti-inflammatory therapeutics.
Asunto(s)
Artritis Gotosa/fisiopatología , Inflamación/prevención & control , Macrófagos Peritoneales/fisiología , Receptor de Melanocortina Tipo 3/fisiología , Receptores de Melanocortina/fisiología , Animales , Artritis Experimental/fisiopatología , Artritis Experimental/prevención & control , Artritis Gotosa/inducido químicamente , Artritis Gotosa/prevención & control , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Activación de Macrófagos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 3/antagonistas & inhibidores , Receptor de Melanocortina Tipo 3/deficiencia , Receptor de Melanocortina Tipo 3/genética , Receptores de Melanocortina/genética , Ácido Úrico/toxicidadRESUMEN
Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.
Asunto(s)
Apetito/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Diabetes Mellitus/metabolismo , Agonistas de los Receptores Histamínicos/farmacología , Imidazoles/uso terapéutico , Obesidad/metabolismo , Tiourea/análogos & derivados , Animales , Diabetes Mellitus/tratamiento farmacológico , Agonistas de los Receptores Histamínicos/uso terapéutico , Insulina/sangre , Leptina/sangre , Ratones , Ratones Noqueados , Obesidad/tratamiento farmacológico , Piperidinas/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Receptores Histamínicos H3/genética , Tiourea/uso terapéuticoRESUMEN
The adipose tissue-derived hormone adiponectin improves insulin sensitivity and its circulating levels are decreased in obesity-induced insulin resistance. Here, we report the generation of a mouse line with a genomic disruption of the adiponectin locus. We aimed to identify whether these mice develop insulin resistance and which are the primary target tissues affected in this model. Using euglycemic/insulin clamp studies, we demonstrate that these mice display severe hepatic but not peripheral insulin resistance. Furthermore, we wanted to test whether the lack of adiponectin magnifies the impairments of glucose homeostasis in the context of a dietary challenge. When exposed to high fat diet, adiponectin null mice rapidly develop glucose intolerance. Specific PPARgamma agonists such as thiazolidinediones (TZDs) improve insulin sensitivity by mechanisms largely unknown. Circulating adiponectin levels are significantly up-regulated in vivo upon activation of PPARgamma. Both TZDs and adiponectin have been shown to activate AMP-activated protein kinase (AMPK) in the same target tissues. We wanted to address whether the ability of TZDs to improve glucose tolerance is dependent on adiponectin and whether this improvement involved AMPK activation. We demonstrate that the ability of PPARgamma agonists to improve glucose tolerance in ob/ob mice lacking adiponectin is diminished. Adiponectin is required for the activation of AMPK upon TZD administration in both liver and muscle. In summary, adiponectin is an important contributor to PPARgamma-mediated improvements in glucose tolerance through mechanisms that involve the activation of the AMPK pathway.
Asunto(s)
Resistencia a la Insulina , Hígado/metabolismo , PPAR gamma/agonistas , Adenilato Quinasa/metabolismo , Adiponectina/deficiencia , Adiponectina/fisiología , Animales , Línea Celular , Grasas de la Dieta/farmacología , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Masculino , Ratones , Músculos/metabolismo , PPAR gamma/metabolismo , Tiazolidinedionas/farmacologíaRESUMEN
A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.
Asunto(s)
Compuestos Aza/farmacología , Ingestión de Alimentos/efectos de los fármacos , Erección Peniana/efectos de los fármacos , Piperazinas/farmacología , Piperidinas/farmacología , Receptor de Melanocortina Tipo 4/agonistas , Animales , Compuestos Aza/síntesis química , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Piperazinas/química , Piperidinas/síntesis química , Unión Proteica , Quinuclidinas/química , Ratas , Ratas Sprague-Dawley , Roedores , Relación Estructura-Actividad , Factores de TiempoRESUMEN
BACKGROUND: The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor pro-opiomelanocortin. A growing body of literature suggests that the MC system modulates neurobiological responses to drugs of abuse. Because ethanol has direct effects on central pro-opiomelanocortin activity, it is possible that MC neuropeptides participate in the control of voluntary ethanol consumption. Here we assessed the possibility that MC receptor (MCR) agonists modulate ethanol intake via the MC3 receptor (MC3R) and/or the MC4 receptor (MC4R) and whether the MCR antagonist AgRP-(83-132) controls ethanol consumption. METHODS: Mc3r-deficient (Mc3r) and wild-type (Mc3r) littermate mice were given intraperitoneal (10 mg/kg) and intracerebroventricular (1.0 microg ICV) doses of melanotan II (MTII), a nonselective MCR agonist. To assess the role of MC4R, C57BL/6J mice were given an ICV infusion of the highly selective MC4R agonist cyclo(NH-CH2-CH2-CO-His-d-Phe-Arg-Trp-Glu)-NH2 (1.0 or 3.0 microg). Finally, naïve C57BL/6J mice were given an ICV infusion of AgRP-(83-132) (0.05 and 1.0 microg). RESULTS: MTII was similarly effective at reducing ethanol drinking in Mc3r-deficient (Mc3r) and wild-type (Mc3r) littermate mice. Furthermore, ICV infusion of the MC4R agonist significantly reduced ethanol drinking, whereas ICV infusion of AgRP-(83-132) significantly increased ethanol drinking in C57BL/6J mice. Neither MTII nor AgRP-(83-132) altered blood ethanol levels at doses that modulated ethanol drinking. CONCLUSIONS: The present results suggest that MC4R, and not MC3R, modulates MCR agonist-induced reduction of ethanol consumption and that ethanol intake is increased by the antagonistic actions of AgRP-(83-132). These findings strengthen the argument that MCR signaling controls ethanol consumption and that compounds directed at MCR may represent promising targets for treating alcohol abuse disorders in addition to obesity.
Asunto(s)
Consumo de Bebidas Alcohólicas/prevención & control , Conducta Animal/efectos de los fármacos , Etanol/efectos adversos , Receptores de Melanocortina/efectos de los fármacos , Proteína Relacionada con Agouti , Animales , Conducta Animal/fisiología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Etanol/sangre , Femenino , Genotipo , Masculino , Ratones , Fragmentos de Péptidos/farmacología , Péptidos Cíclicos/farmacología , Receptor de Melanocortina Tipo 4/efectos de los fármacos , Receptor de Melanocortina Tipo 4/fisiología , Receptores de Melanocortina/fisiología , alfa-MSH/análogos & derivados , alfa-MSH/farmacologíaRESUMEN
Five G-protein-coupled melanocortin receptors (MC(1)-MC(5)) are expressed in mammalian tissues. The melanocortin receptors support diverse physiological functions, including the regulation of hair color, adrenal function, energy homeostasis, feed efficiency, sebaceous gland lipid production and immune and sexual function. The melanocortins (adrenocorticotropic hormone (ACTH), alpha-melanocyte-stimulating hormone (alpha-MSH), beta-MSH and gamma-MSH) are agonist peptide ligands for the melanocortin receptors and these peptides are processed from the pre-prohormone proopiomelanocortin (POMC). Peptide antagonists for the melanocortin MC(1), MC(3) and MC(4) receptors include agouti-related protein (AgRP) and agouti. Diverse lines of evidence, including genetic and pharmacological data obtained in rodents and humans, support a role for the melanocortin MC(3) and MC(4) receptors in the regulation of energy homeostasis. Recent advances in the development of potent and selective peptide and non-peptide melanocortin receptor ligands are anticipated to help unravel the roles for the melanocortin receptors in humans and to accelerate the clinical use of small molecule melanocortin mimetics.
Asunto(s)
Peso Corporal/fisiología , Hormonas Estimuladoras de los Melanocitos/fisiología , Obesidad/fisiopatología , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/uso terapéutico , Peso Corporal/efectos de los fármacos , Expresión Génica , Humanos , Hormonas Estimuladoras de los Melanocitos/genética , Obesidad/tratamiento farmacológico , Receptores de Corticotropina/efectos de los fármacos , Receptores de Corticotropina/genética , Receptores de Corticotropina/fisiología , Receptores de MelanocortinaRESUMEN
Five G-protein-coupled melanocortin receptors (MC(1)-MC(5)) are expressed in mammalian tissues. The melanocortin receptors support diverse physiological functions, including the regulation of hair color, adrenal function, energy homeostasis, feed efficiency, sebaceous gland lipid production and immune and sexual function. The melanocortins (adrenocorticotropic hormone (ACTH), alpha-melanocyte-stimulating hormone (alpha-MSH), beta-MSH and gamma-MSH) are agonist peptide ligands for the melanocortin receptors and these peptides are processed from the pre-prohormone proopiomelanocortin (POMC). Peptide antagonists for the melanocortin MC(1), MC(3) and MC(4) receptors include agouti-related protein (AgRP) and agouti. Diverse lines of evidence, including genetic and pharmacological data obtained in rodents and humans, support a role for the melanocortin MC(3) and MC(4) receptors in the regulation of energy homeostasis. Recent advances in the development of potent and selective peptide and non-peptide melanocortin receptor ligands are anticipated to help unravel the roles for the melanocortin receptors in humans and to accelerate the clinical use of small molecule melanocortin mimetics.
Asunto(s)
Peso Corporal/fisiología , Hormonas Estimuladoras de los Melanocitos/fisiología , Obesidad/fisiopatología , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/uso terapéutico , Peso Corporal/efectos de los fármacos , Expresión Génica , Humanos , Hormonas Estimuladoras de los Melanocitos/genética , Obesidad/tratamiento farmacológico , Receptores de Corticotropina/efectos de los fármacos , Receptores de Corticotropina/genética , Receptores de Corticotropina/fisiología , Receptores de MelanocortinaRESUMEN
Melanin-concentrating hormone (MCH) is a cyclic 19-aa hypothalamic neuropeptide derived from a larger prohormone precursor of MCH (Pmch), which also encodes neuropeptide EI (NEI) and neuropeptide GE (NGE). Pmch-deficient (Pmch-/-) mice are lean, hypophagic, and have an increased metabolic rate. Transgenic mice overexpressing Pmch are hyperphagic and develop mild obesity. Consequently, MCH has been implicated in the regulation of energy homeostasis. The MCH 1 receptor (MCH1R) is one of two recently identified G protein-coupled receptors believed to be responsible for the actions of MCH. We evaluated the physiological role of MCH1R by generating MCH1R-deficient (Mch1r-/-) mice. Mch1r-/- mice have normal body weights, yet are lean and have reduced fat mass. Surprisingly, Mch1r-/- mice are hyperphagic when maintained on regular chow, and their leanness is a consequence of hyperactivity and altered metabolism. Consistent with the hyperactivity, Mch1r-/- mice are less susceptible to diet-induced obesity. Importantly, chronic central infusions of MCH induce hyperphagia and mild obesity in wild-type mice, but not in Mch1r-/- mice. We conclude that MCH1R is a physiologically relevant MCH receptor in mice that plays a role in energy homeostasis through multiple actions on locomotor activity, metabolism, appetite, and neuroendocrine function.