RESUMEN
We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3.
Asunto(s)
Descubrimiento de Drogas , Imidazoles/química , Imidazoles/farmacología , Receptores de Bombesina/agonistas , Animales , Disponibilidad Biológica , Humanos , Imidazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
SAR about the piperidine core in a series of MC4R agonists is described. A number of alkyl substituents that furnish compounds with good affinity and functional potency are reported.
Asunto(s)
Alcanos/farmacología , Piperidinas/química , Piperidinas/farmacología , Receptor de Melanocortina Tipo 4/agonistas , Receptor de Melanocortina Tipo 4/metabolismo , Alcanos/síntesis química , Alcanos/química , Amidas/química , Humanos , Estructura Molecular , Nitrilos/química , Piperidinas/síntesis química , Relación Estructura-Actividad , Tetrazoles/químicaRESUMEN
During an effort to search for more potent growth hormone secretagogues, we discovered a class of compounds of which the best compound 8 was 7-fold more active in vitro than the best compound in the series we revealed before [Tata, J. R.; Lu, Z.; Jacks, T. M.; Schleim, K. D.; Cheng, K.; Wei, L.; Chan, W.-S.; Butler, B.; Tsou, N.; Leung, K.; Chiu, S.-H. L.; Hickey, G. J.; Smith, R. G.; Patchett, A. A. Bioorg. Med. Chem. Lett.1997, 7, 2319.]. Animal studies show that compound 8 can stimulate growth hormone release at the oral dose as low as 0.06 mpk. Chemistry and biological studies are discussed.
Asunto(s)
Química Farmacéutica/métodos , Hormona del Crecimiento/química , Hormona del Crecimiento/síntesis química , Administración Oral , Amidas/química , Aminas/química , Animales , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Hormona del Crecimiento/metabolismo , Indoles/farmacología , Modelos Químicos , Hipófisis/química , Hipófisis/citología , Hipófisis/efectos de los fármacos , Ratas , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Somatostatin inhibits both glucagon and insulin secretion. Glucagon significantly contributes to hyperglycemia in type 2 diabetes. Despite its function in the inhibition of glucagon secretion, somatostatin fails to reduce hyperglycemia in type 2 diabetes, due to a parallel suppression of insulin secretion. Five pharmacologically distinct somatostatin receptor subtypes (sst(1)-sst(5)) mediate the effects of somatostatin on a cellular level. Pancreatic A cells express sst(2), whereas B cells express sst(5). In this study, we describe a novel approach to the treatment of type 2 diabetes using a highly sst(2)-selective, nonpeptide agonist (compound 1). Compound 1 effectively inhibited glucagon secretion from pancreatic islets isolated from wild-type mice, whereas glucagon secretion from sst(2)-deficient islets was not suppressed. Compound 1 did not influence nonfasted insulin concentration. In sst(2)-deficient mice, compound 1 did not have any effects on glucagon or glucose levels, confirming its sst(2) selectivity. In animal models of type 2 diabetes in the nonfasted state, circulating glucagon and glucose levels were decreased after treatment with compound 1. In the fasting state, compound 1 lowered blood glucose by approximately 25%. In summary, small-molecule sst(2)-selective agonists that suppress glucagon secretion offer a novel approach toward the development of orally bioavailable drugs for treatment of type 2 diabetes.
Asunto(s)
Hipoglucemiantes/farmacología , Receptores de Somatostatina/agonistas , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Perros , Glucagón/metabolismo , Hormona del Crecimiento/metabolismo , Técnicas In Vitro , Insulina/metabolismo , Insulina/farmacología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Ratas , Receptores de Somatostatina/genéticaRESUMEN
Design and synthesis of potent MC4 selective agonists based on cyclohexylpiperidine derived cyclic urea, oxazolidinones, and sulfonamide based privileged structures are disclosed.
Asunto(s)
Diseño de Fármacos , Receptor de Melanocortina Tipo 4/agonistas , Receptor de Melanocortina Tipo 4/metabolismo , Humanos , Ligandos , Estructura Molecular , Sensibilidad y Especificidad , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The melanocortin subtype-4 receptor (MC4R) has been implicated in the control of feeding behavior and body weight regulation. A series of tetrapeptides, based on Tic-DPhe-Arg-Trp-NH2-a mimic of the putative message sequence "His-Phe-Arg-Trp" and modified at the DPhe position, were prepared and pharmacologically characterized for potency and selectivity. Substitution of His with Tic gave peptides with significant increases in selectivity. The effects of the substitution pattern of DPhe were investigated and it has significant influences on potency and the level of the maximum cAMP accumulation. Intracerebroventricular administration of peptide 10 induced significant inhibition of cumulative overnight food intake and feeding duration in rats.
Asunto(s)
Depresores del Apetito/administración & dosificación , Depresores del Apetito/síntesis química , Ingestión de Alimentos/efectos de los fármacos , Oligopéptidos/administración & dosificación , Oligopéptidos/síntesis química , Receptor de Melanocortina Tipo 4/metabolismo , Animales , Depresores del Apetito/metabolismo , Unión Competitiva , Células CHO , Cricetinae , Cricetulus , Ingestión de Alimentos/fisiología , Humanos , Masculino , Modelos Moleculares , Oligopéptidos/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
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
The discovery of 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid analogs as potent human melanocortin-4 selective agonists is described.
Asunto(s)
Ácidos Carboxílicos/farmacología , Receptor de Melanocortina Tipo 4/agonistas , Tetrahidroisoquinolinas/química , Tetrahidronaftalenos/farmacología , Humanos , Conformación Molecular , Imitación Molecular , Unión Proteica/efectos de los fármacos , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-ActividadRESUMEN
We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. The 5- and 6-alkylated piperazine compounds exhibit low bioactivation potential as measured by covalent binding in microsome preparations.
Asunto(s)
Piperazinas/química , Piperazinas/farmacología , Receptor de Melanocortina Tipo 4/agonistas , Humanos , Piperazinas/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-ActividadRESUMEN
We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. Further in vivo development of lead agonist, MB243, is disclosed.
Asunto(s)
Piperazinas/farmacología , Piperidinas/farmacología , Receptor de Melanocortina Tipo 4/agonistas , Animales , Perros , Disfunción Eréctil/tratamiento farmacológico , Haplorrinos , Masculino , Ratones , Obesidad/tratamiento farmacológico , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , RatasRESUMEN
A new series of growth hormone secretagogues have been discovered. The best compound, 26j, shows excellent ability to release growth hormone both in vitro and in vivo. The synthesis and biological activity of these compounds are discussed.
Asunto(s)
Hormona del Crecimiento/metabolismo , Piperidinas/síntesis química , Piperidinas/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Perros , Hormona del Crecimiento/análisis , Piperidinas/farmacología , Hipófisis/citología , Ratas , Relación Estructura-ActividadAsunto(s)
Distinciones y Premios , Productos Biológicos/historia , Química Orgánica , Diseño de Fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/síntesis química , Inhibidores de la Enzima Convertidora de Angiotensina/historia , Antihipertensivos/síntesis química , Antihipertensivos/historia , Benzodiazepinonas/síntesis química , Benzodiazepinonas/historia , Productos Biológicos/química , Historia del Siglo XX , Historia del Siglo XXI , Inhibidores de Hidroximetilglutaril-CoA Reductasas/síntesis química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/historia , Lovastatina/síntesis química , Lovastatina/historia , Estados UnidosRESUMEN
Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.
Asunto(s)
Isoquinolinas/síntesis química , Receptores de Corticotropina/agonistas , Tetrahidroisoquinolinas , Triazoles/síntesis química , Animales , Unión Competitiva , Disponibilidad Biológica , Células CHO , Cricetinae , Perros , Ingestión de Alimentos/efectos de los fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/farmacología , Conformación Molecular , Erección Peniana/efectos de los fármacos , Ratas , Receptor de Melanocortina Tipo 3 , Receptor de Melanocortina Tipo 4 , Receptores de Melanocortina , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
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.