RESUMEN
A search for a suitable replacement for the central norbornyl scaffold presented in the recently disclosed novel FLAP inhibitors is herein described, as well as the SAR study performed on the endo and exo-aryl groups.
Asunto(s)
Inhibidores de Proteína Activante de 5-Lipoxigenasa/síntesis química , Proteínas Activadoras de la 5-Lipooxigenasa/química , Alcanos/síntesis química , Antialérgicos/síntesis química , Derivados del Benceno/síntesis química , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacocinética , Inhibidores de Proteína Activante de 5-Lipoxigenasa/farmacología , Proteínas Activadoras de la 5-Lipooxigenasa/metabolismo , Alcanos/farmacocinética , Alcanos/farmacología , Animales , Antialérgicos/farmacocinética , Antialérgicos/farmacología , Derivados del Benceno/farmacocinética , Derivados del Benceno/farmacología , Humanos , Concentración 50 Inhibidora , Inyecciones Intravenosas , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The design, synthesis, and binding activity of ring constrained analogs of the acyclic cannabinoid-1 receptor (CB1R) inverse agonist taranabant 1 are described. The initial inspiration for these taranabant derivatives was its conformation 1a, determined by (1)H NMR, X-ray, and molecular modeling. The constrained analogs were all much less potent than their acyclic parent structure. The results obtained are discussed in the context of a predicted binding of 1 to a homology model of CB1R.
Asunto(s)
Amidas/química , Fármacos Antiobesidad/síntesis química , Piridinas/química , Receptor Cannabinoide CB1/química , Amidas/síntesis química , Amidas/farmacología , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Simulación por Computador , Humanos , Modelos Moleculares , Conformación Molecular , Unión Proteica , Piridinas/síntesis química , Piridinas/farmacología , Receptor Cannabinoide CB1/metabolismoRESUMEN
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.
Asunto(s)
Naftiridinas/química , Piridinas/química , Receptor Cannabinoide CB1/agonistas , Pérdida de Peso/efectos de los fármacos , Administración Oral , Animales , Ingestión de Alimentos , Humanos , Naftiridinas/síntesis química , Naftiridinas/farmacología , Farmacocinética , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Receptor Cannabinoide CB1/efectos de los fármacos , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Diseño de Fármacos , Furanos/síntesis química , Piridinas/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Benzopiranos , Perros , Furanos/química , Furanos/farmacología , Haplorrinos , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Noqueados , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Ratas , Receptor Cannabinoide CB1/genética , Relación Estructura-ActividadRESUMEN
PURPOSE: The in vitro and in vivo evaluation of the selective, high affinity (human CB1 IC(50) 0.49 nM) inverse agonist CB1R tracer [(11)C]CB-119, a close analog of the previously disclosed [(18)F]MK-9470, was undertaken. PROCEDURES: [(11)C]CB-119 was synthesized with high specific activity by alkylation of a phenolic precursor with [(11)C]methyl iodide. In vitro autoradiographic studies using rhesus brain slices were carried out using [(3)H]CB-119, and in vivo imaging studies were carried out using [(11)C]CB-119 in rhesus monkeys under baseline and blocked conditions. RESULTS: Autoradiographic studies in rhesus brain showed the expected distribution pattern for CB1R with highest binding in the cerebral cortex, cerebellum, caudate/putamen, globus pallidus, substantia nigra, and hippocampus. Lower binding was seen in the posterior hypothalamus, ventral tegmental area, and periventricular gray area, and the lowest binding was in the thalamic nuclei. The binding of [(3)H]CB-119 was fully blocked by the addition of 10 microM CB-119. Rhesus positron emission tomography imaging studies showed very good brain uptake and a distribution pattern consistent with that seen in the autoradiographic studies. The kinetics of tracer uptake was slow. The brain uptake was blocked by pretreatment with taranabant, a CB1R inverse agonist. The specific signal (total/nonspecific) in rhesus putamen at 90 min was approximately 6:1. CONCLUSIONS: [(11)C]CB-119 is a suitable tracer for imaging central CB1 receptors.
Asunto(s)
Amidas/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía de Emisión de Positrones , Piridinas/metabolismo , Radiofármacos/metabolismo , Receptor Cannabinoide CB1/metabolismo , Animales , Autorradiografía , Radioisótopos de Carbono , Ligandos , Macaca mulatta , Unión Proteica , Receptor Cannabinoide CB1/agonistas , Distribución Tisular , Tritio/químicaRESUMEN
The human GnRH receptor (hGnRHR), a G protein-coupled receptor, is a useful model for studying pharmacological chaperones (pharmacoperones), drugs that rescue misfolded and misrouted protein mutants and restore them to function. This technique forms the basis of a therapeutic approach of rescuing mutants associated with human disease and restoring them to function. The present study relies on computational modeling, followed by site-directed mutagenesis, assessment of ligand binding, effector activation, and confocal microscopy. Our results show that two different chemical classes of pharmacoperones act to stabilize hGnRHR mutants by bridging residues D(98) and K(121). This ligand-mediated bridge serves as a surrogate for a naturally occurring and highly conserved salt bridge (E(90)-K(121)) that stabilizes the relation between transmembranes 2 and 3, which is required for passage of the receptor through the cellular quality control system and to the plasma membrane. Our model was used to reveal important pharmacophoric features, and then identify a novel chemical ligand, which was able to rescue a D(98) mutant of the hGnRHR that could not be rescued as effectively by previously known pharmacoperones.
Asunto(s)
Modelos Moleculares , Chaperonas Moleculares/metabolismo , Receptores Acoplados a Proteínas G , Receptores LHRH , Animales , Bovinos , Membrana Celular/metabolismo , Simulación por Computador , Humanos , Ligandos , Estructura Molecular , Mutagénesis Sitio-Dirigida , Mutación , Unión Proteica , Conformación Proteica , Transporte de Proteínas/fisiología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores LHRH/genética , Receptores LHRH/metabolismoRESUMEN
Discovery of a series of tert-butyl pyrrolidine derived, potent and orally bioavailable melanocortin receptor subtype-4 (MC4R) selective modulators is disclosed.
Asunto(s)
Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Receptor de Melanocortina Tipo 4/agonistas , Administración Oral , Humanos , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , TelomerasaRESUMEN
X-ray crystallographic, NMR spectroscopic, and computational studies of taranabant afforded similar low-energy conformers with a significant degree of rigidity along the C11-N13-C14-C16-C17 backbone but with more flexibility around bonds C8-C11 and C8-O7. Mutagenesis and docking studies suggested that taranabant and rimonabant shared the same general binding area of CB1R but with significant differences in detailed interactions. Similar to rimonabant, taranabant interacted with a cluster of aromatic residues (F(3.36)200, W(5.43)279, W(6.48)356, and Y(5.39)275) through the two phenyl rings and with F(2.57)170 and L(7.42)387 through the CF 3-Pyr ring. The notable distinction between taranabant and rimonabant was that taranabant was hydrogen-bonded with S(7.39)383 but not with K(3.28)192, while rimonabant was hydrogen-bonded with K(3.28)192 but not with S(7.39)383. The strong hydrogen bonding between the amide NH of taranabant and hydroxyl of S(7.39)383 was key to the superior affinity of taranabant to CB1R.
Asunto(s)
Amidas/química , Amidas/farmacología , Piridinas/química , Piridinas/farmacología , Receptor Cannabinoide CB1/agonistas , Secuencia de Aminoácidos , Animales , Sitios de Unión , Células CHO , Células Cultivadas , Simulación por Computador , Cricetinae , Cricetulus , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/normas , Modelos Moleculares , Conformación Molecular , Datos de Secuencia Molecular , Estructura Molecular , Mutagénesis Sitio-Dirigida , Receptor Cannabinoide CB1/química , Receptor Cannabinoide CB1/genética , Estándares de Referencia , Alineación de Secuencia , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Fármacos Antiobesidad/farmacología , Imidazoles/farmacología , Obesidad/tratamiento farmacológico , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Administración Oral , Animales , Autorradiografía , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dexfenfluramina/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Agonismo Inverso de Drogas , Ingestión de Alimentos/efectos de los fármacos , Humanos , Imidazoles/administración & dosificación , Técnicas In Vitro , Masculino , Ratones , Ratones Noqueados , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB2/agonistasRESUMEN
The discovery of a structurally distinct cannabinoid-1 receptor (CB1R) positron emission tomography tracer is described. Starting from an acyclic amide CB1R inverse agonist (1) as the lead compound, an efficient route to introduce 18F to the molecule was developed. Further optimization focused on reducing the lipophilicity and increasing the CB1R affinity. These efforts led to the identification of [18F]-16 that exhibited good brain uptake and an excellent signal-to-noise ratio in rhesus monkeys.
Asunto(s)
Amidas/síntesis química , Radioisótopos de Flúor , Piridinas/síntesis química , Radiofármacos/síntesis química , Receptor Cannabinoide CB1/metabolismo , Amidas/química , Amidas/farmacocinética , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Macaca mulatta , Tomografía de Emisión de Positrones , Piridinas/química , Piridinas/farmacocinética , Ensayo de Unión Radioligante , Radiofármacos/química , Radiofármacos/farmacocinética , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
All reported GnRH receptor mutants (causing human hypogonadotropic hypogonadism) are misfolded proteins that cannot traffic to the plasma membrane. Pharmacoperones correct misfolding and rescue mutants, routing them to the plasma membrane where they regain function. Because pharmacoperones are often peptidomimetic antagonists, these must be removed for receptor function after rescue; in vivo this necessitates pulsatile pharmacoperone administration. As an antecedent to in vivo studies, we determined whether pharmacoperones need to be present at the time of synthesis or whether previously misfolded proteins could be refolded and rescued. Accordingly, we blocked either protein synthesis or intra-cellular transport. Biochemical and morphological studies using 12 mutants and 10 pharmacoperones representing three different chemical classes show that previously synthesized mutant proteins, retained by the quality control system (QCS), are rescued by pharmacoperones, showing that pharmacoperone administration in vivo likely need not consider whether the target protein is being synthesized at the time of drug administration.
Asunto(s)
Chaperonas Moleculares/farmacología , Pliegue de Proteína , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores LHRH/metabolismo , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Células COS , Chlorocebus aethiops , Evaluación Preclínica de Medicamentos , Células HeLa , Humanos , Indoles/farmacología , Inositol/farmacología , Imitación Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Transporte de Proteínas/efectos de los fármacos , Piridinas/farmacología , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores LHRH/química , Receptores LHRH/genética , TransfecciónRESUMEN
[(18)F]MK-9470 is a selective, high-affinity, inverse agonist (human IC(50), 0.7 nM) for the cannabinoid CB1 receptor (CB1R) that has been developed for use in human brain imaging. Autoradiographic studies in rhesus monkey brain showed that [(18)F]MK-9470 binding is aligned with the reported distribution of CB1 receptors with high specific binding in the cerebral cortex, cerebellum, caudate/putamen, globus pallidus, substantia nigra, and hippocampus. Positron emission tomography (PET) imaging studies in rhesus monkeys showed high brain uptake and a distribution pattern generally consistent with that seen in the autoradiographic studies. Uptake was blocked by pretreatment with a potent CB1 inverse agonist, MK-0364. The ratio of total to nonspecific binding in putamen was 4-5:1, indicative of a strong specific signal that was confirmed to be reversible via displacement studies with MK-0364. Baseline PET imaging studies in human research subject demonstrated behavior of [(18)F]MK-9470 very similar to that seen in monkeys, with very good test-retest variability (7%). Proof of concept studies in healthy young male human subjects showed that MK-0364, given orally, produced a dose-related reduction in [(18)F]MK-9470 binding reflecting CB1R receptor occupancy by the drug. Thus, [(18)F]MK-9470 has the potential to be a valuable, noninvasive research tool for the in vivo study of CB1R biology and pharmacology in a variety of neuropsychiatric disorders in humans. In addition, it allows demonstration of target engagement and noninvasive dose-occupancy studies to aid in dose selection for clinical trials of CB1R inverse agonists.
Asunto(s)
Encéfalo/anatomía & histología , Tomografía de Emisión de Positrones/métodos , Trazadores Radiactivos , Receptor Cannabinoide CB1/ultraestructura , Amidas/metabolismo , Animales , Autorradiografía , Encéfalo/metabolismo , Radioisótopos de Flúor , Humanos , Procesamiento de Imagen Asistido por Computador , Macaca mulatta , Masculino , Estructura Molecular , Piridinas/metabolismo , Receptor Cannabinoide CB1/metabolismoRESUMEN
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.
Asunto(s)
Amidas/farmacología , Fármacos Antiobesidad/farmacología , Obesidad/tratamiento farmacológico , Piridinas/farmacología , Receptor Cannabinoide CB1/metabolismo , Amidas/química , Amidas/metabolismo , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/metabolismo , Unión Competitiva/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Células CHO , Colforsina/farmacología , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Ciclohexanoles/farmacología , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Humanos , Indoles/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estructura Molecular , Obesidad/metabolismo , Obesidad/fisiopatología , Piperidinas/metabolismo , Piridinas/química , Piridinas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/fisiología , TransfecciónRESUMEN
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.
Asunto(s)
Moduladores de Receptores de Cannabinoides/síntesis química , Receptor Cannabinoide CB1/efectos de los fármacos , Sulfonamidas/síntesis química , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacología , Química Encefálica , Moduladores de Receptores de Cannabinoides/farmacología , Humanos , Hipotermia/tratamiento farmacológico , Concentración 50 Inhibidora , Farmacocinética , Ratas , Receptor Cannabinoide CB1/agonistas , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
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.
Asunto(s)
Química Farmacéutica/métodos , Piridinas/química , Piridinas/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Conducta Animal/efectos de los fármacos , Diseño de Fármacos , Conducta Alimentaria/efectos de los fármacos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Temperatura , Tolueno/químicaRESUMEN
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.
Asunto(s)
Fármacos Antiobesidad/farmacología , Cannabinoides/farmacología , Obesidad/tratamiento farmacológico , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Peso Corporal/efectos de los fármacos , Cannabinoides/síntesis química , Cannabinoides/química , AMP Cíclico/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Ratas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/metabolismoRESUMEN
Structure-activity relationships of a 4-aminoquinoline MCH1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4-, and 6-positions of the original HTS hit. Improvements to the original screening lead included lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl, and hydrocinnamyl carboxamides at the 6-position. Modifications of the 4-amino group were not well tolerated.
Asunto(s)
Aminoquinolinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Aminoquinolinas/síntesis química , Aminoquinolinas/química , Unión Competitiva , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Técnicas In Vitro , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of 2-aminoquinoline compounds was prepared and evaluated in MCH1R binding and functional antagonist assays. Small dialkyl, methylalkyl, methylcycloalkyl, and cyclic amines were tolerated at the quinoline 2-position. The in vivo efficacy of compound 12 was explored and compared to that of a related inactive analog to determine their effects on food intake and body weight in rodents.
Asunto(s)
Quinolinas/farmacología , Quinuclidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Unión Competitiva , Bioensayo , Ingestión de Alimentos , Metabolismo Energético/efectos de los fármacos , Humanos , Masculino , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Quinuclidinas/síntesis química , Quinuclidinas/química , Ratas , Ratas Sprague-Dawley , Receptores de Somatostatina/química , Receptores de Somatostatina/genética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of 3-aryl-4-hydroxyquinolin-2(1H)-ones with fatty acid synthase inhibitory activity was prepared. Starting from a derivative with an IC(50) = 1.4 microM, SAR studies led to compounds with more than 70-fold increase in potency (IC(50) < 20 nM).
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Ácido Graso Sintasas/antagonistas & inhibidores , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Inhibidores Enzimáticos/química , Ácido Graso Sintasas/metabolismo , Humanos , Hidroxiquinolinas/síntesis química , Malonatos/química , Microondas , Estructura Molecular , Quinolinas/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
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.