RESUMO
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.
Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/síntese química , Proteínas Ativadoras de 5-Lipoxigenase/química , Alcanos/síntese química , Antialérgicos/síntese química , Derivados de Benzeno/síntese química , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacocinética , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Alcanos/farmacocinética , Alcanos/farmacologia , Animais , Antialérgicos/farmacocinética , Antialérgicos/farmacologia , Derivados de Benzeno/farmacocinética , Derivados de Benzeno/farmacologia , Humanos , Concentração Inibidora 50 , Injeções Intravenosas , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer disease (AD) and likely contributes to neuropathology through various pathways. Here we report that the intracellular trafficking of apoE4 is impaired in Neuro-2a cells and primary neurons, as shown by measuring fluorescence recovery after photobleaching. In Neuro-2a cells, more apoE4 than apoE3 molecules remained immobilized in the endoplasmic reticulum (ER) and the Golgi apparatus, and the lateral motility of apoE4 was significantly lower in the Golgi apparatus (but not in the ER) than that of apoE3. Likewise, the immobile fraction was larger, and the lateral motility was lower for apoE4 than apoE3 in mouse primary hippocampal neurons. ApoE4 with the R61T mutation, which abolishes apoE4 domain interaction, was less immobilized, and its lateral motility was comparable with that of apoE3. The trafficking impairment of apoE4 was also rescued by disrupting domain interaction with the small-molecule structure correctors GIND25 and PH002. PH002 also rescued apoE4-induced impairments of neurite outgrowth in Neuro-2a cells and dendritic spine development in primary neurons. ApoE4 did not affect trafficking of amyloid precursor protein, another AD-related protein, through the secretory pathway. Thus, domain interaction renders more newly synthesized apoE4 molecules immobile and slows their trafficking along the secretory pathway. Correcting the pathological structure of apoE4 by disrupting domain interaction is a potential therapeutic approach to treat or prevent AD related to apoE4.
Assuntos
Apolipoproteína E4/metabolismo , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Linhagem Celular Tumoral , Retículo Endoplasmático/metabolismo , Recuperação de Fluorescência Após Fotodegradação , Complexo de Golgi/metabolismo , Hipocampo/citologia , Humanos , Camundongos , Modelos Biológicos , Mutação , Neurônios/metabolismoRESUMO
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.
Assuntos
Amidas/química , Fármacos Antiobesidade/síntese química , Piridinas/química , Receptor CB1 de Canabinoide/química , Amidas/síntese química , Amidas/farmacologia , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Simulação por Computador , Humanos , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Piridinas/síntese química , Piridinas/farmacologia , Receptor CB1 de Canabinoide/metabolismoRESUMO
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
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
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.
Assuntos
Amidas/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons , Piridinas/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Animais , Autorradiografia , Radioisótopos de Carbono , Ligantes , Macaca mulatta , Ligação Proteica , Receptor CB1 de Canabinoide/agonistas , Distribuição Tecidual , Trítio/químicaRESUMO
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.
Assuntos
Modelos Moleculares , Chaperonas Moleculares/metabolismo , Receptores Acoplados a Proteínas G , Receptores LHRH , Animais , Bovinos , Membrana Celular/metabolismo , Simulação por Computador , Humanos , Ligantes , Estrutura Molecular , Mutagênese Sítio-Dirigida , Mutação , Ligação Proteica , Conformação Proteica , Transporte Proteico/fisiologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores LHRH/genética , Receptores LHRH/metabolismoRESUMO
Discovery of a series of tert-butyl pyrrolidine derived, potent and orally bioavailable melanocortin receptor subtype-4 (MC4R) selective modulators is disclosed.
Assuntos
Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Receptor Tipo 4 de Melanocortina/agonistas , Administração Oral , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , TelomeraseRESUMO
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.
Assuntos
Amidas/química , Amidas/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptor CB1 de Canabinoide/agonistas , Sequência de Aminoácidos , Animais , Sítios de Ligação , Células CHO , Células Cultivadas , Simulação por Computador , Cricetinae , Cricetulus , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/normas , Modelos Moleculares , Conformação Molecular , Dados de Sequência Molecular , Estrutura Molecular , Mutagênese Sítio-Dirigida , Receptor CB1 de Canabinoide/química , Receptor CB1 de Canabinoide/genética , Padrões de Referência , Alinhamento de Sequência , Relação Estrutura-AtividadeRESUMO
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 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.
Assuntos
Amidas/síntese química , Radioisótopos de Flúor , Piridinas/síntese química , Compostos Radiofarmacêuticos/síntese química , Receptor CB1 de Canabinoide/metabolismo , Amidas/química , Amidas/farmacocinética , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Humanos , Macaca mulatta , Tomografia por Emissão de Pósitrons , Piridinas/química , Piridinas/farmacocinética , Ensaio Radioligante , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Chaperonas Moleculares/farmacologia , Dobramento de Proteína , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores LHRH/metabolismo , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células COS , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Células HeLa , Humanos , Indóis/farmacologia , Inositol/farmacologia , Mimetismo Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Transporte Proteico/efeitos dos fármacos , Piridinas/farmacologia , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores LHRH/química , Receptores LHRH/genética , TransfecçãoRESUMO
[(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.
Assuntos
Encéfalo/anatomia & histologia , Tomografia por Emissão de Pósitrons/métodos , Traçadores Radioativos , Receptor CB1 de Canabinoide/ultraestrutura , Amidas/metabolismo , Animais , Autorradiografia , Encéfalo/metabolismo , Radioisótopos de Flúor , Humanos , Processamento de Imagem Assistida por Computador , Macaca mulatta , Masculino , Estrutura Molecular , Piridinas/metabolismo , Receptor CB1 de Canabinoide/metabolismoRESUMO
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
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.
Assuntos
Aminoquinolinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Aminoquinolinas/síntese química , Aminoquinolinas/química , Ligação Competitiva , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Técnicas In Vitro , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Quinolinas/farmacologia , Quinuclidinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Ligação Competitiva , Bioensaio , Ingestão de Alimentos , Metabolismo Energético/efeitos dos fármacos , Humanos , Masculino , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Quinuclidinas/síntese química , Quinuclidinas/química , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/química , Receptores de Somatostatina/genética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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).