RESUMO
A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure-activity relationship studies led to the identification of highly potent CRF1 receptor antagonists 14a (IC50=0.74 nM) and 14b (IC50=1.9 nM). The synthesis, structure-activity relationships and in vitro metabolic stability properties of compounds in this series will be described.
Assuntos
Carbamatos/farmacologia , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Carbamatos/síntese química , Carbamatos/metabolismo , Linhagem Celular Tumoral , Humanos , Microssomos Hepáticos/metabolismo , Pirazinas/síntese química , Pirazinas/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
Racemic 5-(trans-2-aminomethylcyclopropyl)indoles, 5-(trans-2-aminomethylcyclopentyl) indoles, and 5-(cis-2-aminomethylcyclopentyl)indoles were synthesized and evaluated as selective serotonin reuptake inhibitors. These analogs followed SAR trends similar to those previously reported for 3-cycloalkyl substituted indoles. The most potent analogs exhibited single digit nanomolar inhibition at the human serotonin transporter but were 10-fold less active than the previously reported compounds.
Assuntos
Metilaminas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Metilaminas/síntese química , Metilaminas/química , Conformação Molecular , Estrutura Molecular , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/química , Relação Estrutura-AtividadeRESUMO
A series of pyrazinones were prepared and evaluated as potential CRF(1)R PET imaging agents. Optimization of their CRF(1)R binding potencies and octanol-phosphate buffer phase distribution coefficients are discussed herein.
Assuntos
Tomografia por Emissão de Pósitrons , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Encéfalo , Humanos , Estrutura Molecular , Pirazinas/química , Ratos , Receptores de Hormônio Liberador da Corticotropina/químicaRESUMO
Based on a favorable balance between CRF-R1 affinity, lipophilicity and metabolic stability, compound 10 was evaluated for potential development as PET radioligand. Compound [(18)F]10 was prepared with high radiochemical purity and showed promising binding properties in rat brain imaging experiments.
Assuntos
Compostos de Anilina/química , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons , Pirazinas/química , Pirazóis/química , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Flúor/sangue , Imageamento Tridimensional , Estrutura Molecular , Pirazóis/metabolismo , Ratos , Distribuição TecidualRESUMO
A series of N-fluoroalkyl-8-(6-methoxy-2-methylpyridin-3-yl)-2,7-dimethyl-N-alkylpyrazolo[1,5-a][1,3,5]triazin-4-amines were prepared and evaluated as potential CRF(1)R PET imaging agents. Optimization of their CRF(1)R binding potencies and octanol-phosphate buffer phase distribution coefficients resulted in discovery of analog 7e (IC(50)=6.5 nM, logD=3.5).
Assuntos
Aminas/química , Pirazóis/química , Receptores de Hormônio Liberador da Corticotropina/química , Triazinas/química , Aminas/síntese química , Cristalografia por Raios X , Conformação Molecular , Tomografia por Emissão de Pósitrons , Pirazóis/síntese química , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Triazinas/síntese químicaRESUMO
Substituted 1-tosyl-3-vinylindoles undergo [3+2] dipolar cycloaddition with cyclic nitrones to afford substituted isoxazoles in good yield and high diastereoselectivity. The cycloadducts were readily converted in 4 steps into ring constrained homotryptamine analogs. These analogs exhibited excellent binding affinity for the human serotonin transporter (hSERT). Indoles bearing a 5-cyano group and a pendent ethyl(tetrahydroisoquinoline) moiety at the 3-position displayed the best potency for hSERT and high selectivity versus hDAT and hNET.
Assuntos
Indóis/síntese química , Indóis/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/síntese química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Triptaminas/síntese química , Triptaminas/metabolismo , Linhagem Celular , Cristalografia por Raios X , Humanos , Ligação Proteica/fisiologiaRESUMO
A series of N(3)-pyridylpyrazinones was investigated as corticotropin-releasing factor-1 receptor antagonists. It was observed that the binding affinity of analogues containing a pyridyl group was influenced not only by the substitution pattern on the pyridyl group, but also by the pK(a) of the pyridyl nitrogen. Analogues containing a novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group were among the most potent N(3)-pyridylpyrazinones synthesized. The synthesis and SAR of N(3)-pyridylpyrazinones is described herein.
Assuntos
Pirazinas/síntese química , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Pirazinas/química , Relação Estrutura-AtividadeRESUMO
A series of racemic 3-(trans-2-aminomethylcyclopentyl)indoles was synthesized and found to have potent binding to the human serotonin transporter (hSERT). The most active analog was synthesized stereospecifically and the active enantiomer was shown to have high affinity binding to hSERT.
Assuntos
Indóis/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Triptaminas/química , Animais , Antidepressivos/química , Química Farmacêutica/métodos , Ciclopentanos/química , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Químicos , Ligação Proteica , Ratos , Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/química , Relação Estrutura-AtividadeRESUMO
Treatment of obesity is still a large unmet medical need. Neuropeptide Y is the most potent orexigenic peptide in the animal kingdom. Its five cloned G-protein couple receptors are all implicated in the regulation of energy homeostasis evidenced by overexpression or deletion of neuropeptide Y or its receptors. Neuropeptide Y most likely exerts its orexigenic activity via the neuropeptide Y(1) and neuropeptide Y(5) receptors, although the involvement of the neuropeptide Y(2) and neuropeptide Y(4) receptors are also gaining importance. The lack of potent, selective, and brain penetrable pharmacologic agents at these receptors made our understanding of the modulation of food intake by neuropeptide Y-ergic agents elusive. BMS-193885 (1,4-dihydro-[3-[[[[3-[4-(3-methoxyphenyl)-1-piperidinyl]propyl]amino] carbonyl]amino]phenyl]-2,6-dimethyl-3,5-pyridinedicarboxylic acid, dimethyl ester) is a potent and selective neuropeptide Y(1) receptor antagonist. BMS-193885 has 3.3 nM affinity at the neuropeptide Y(1) receptor, acting competitively at the neuropeptide Y binding site. BMS-193885 increased the K(d) of [(125)I]PeptideYY from 0.35 nM to 0.65 nM without changing the B(max) (0.16 pmol/mg of protein) in SK-N-MC cells that endogenously express the neuropeptide Y(1) receptor. It is also found to be a full antagonist with an apparent K(b) of 4.5 nM measured by reversal of forskolin (FK)-stimulated inhibition of cAMP production by neuropeptide Y. Pharmacological profiling showed that BMS-193885 has no appreciable affinity at the other neuropeptide Y receptors, and is also 200-fold less potent at the alpha(2) adrenergic receptor. Testing the compound in a panel of 70 G-protein coupled receptors and ion channels resulted in at least 200-fold or greater selectivity, with the exception of the sigma(1) receptor, where the selectivity was 100-fold. When administered intracerebroventricularly or directly into the paraventricular nucleus of the hypothalamus, it blocked neuropeptide Y-induced food intake in rats. Intraperitoneal administration of BMS-193885 (10 mg/kg) also reduced one-hour neuropeptide Y-induced food intake in satiated rats, as well as spontaneous overnight food consumption. Chronic administration of BMS-193885 (10 mg/kg) i.p. for 44 days significantly reduced food intake and the rate of body weight gain compared to vehicle treated control without developing tolerance or affecting water intake. These results provide supporting evidence that BMS-193885 reduces food intake and body weight via inhibition of the central neuropeptide Y(1) receptor. BMS-193885 has no significant effect of locomotor activity up to 20 mg/kg dose after 1 h of treatment. It also showed no activity in the elevated plus maze when tested after i.p. and i.c.v. administration, indicating that reduction of food intake is unrelated to anxious behavior. BMS-193885 has good systemic bioavailability and brain penetration, but lacks oral bioavailability. The compound had no serious cardiovascular adverse effect in rats and dogs up to 30 and 10 mg/kg dose, respectively, when dosed intravenously. These data demonstrate that BMS-193885 is a potent, selective, brain penetrant Y(1) receptor antagonist that reduces food intake and body weight in animal models of obesity both after acute and chronic administration. Taken together the data suggest that a potent and selective neuropeptide Y(1) receptor antagonist might be an efficacious treatment for obesity in humans.
Assuntos
Depressores do Apetite/farmacologia , Di-Hidropiridinas/farmacologia , Compostos de Fenilureia/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Di-Hidropiridinas/farmacocinética , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Injeções Intraventriculares , Masculino , Neuropeptídeo Y/fisiologia , Compostos de Fenilureia/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans. The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis stereochemistry was (1R,2S)-cis. Substitution of the indole N-1 position with methyl or ethyl groups gave a 10- to 30-fold decrease in affinity for hSERT, suggesting either a hydrogen-bonding interaction or limited steric tolerance in the region of the indole nitrogen. Compound (+)-12a demonstrated potent hSERT binding (Ki = 0.18 nM) in vitro and was more than 1000-fold less potent at hDAT, hNET, 5-HT1A, and 5-HT6. In vivo, (+)-12a produced robust, dose-dependent increases in extracellular serotonin in rat frontal cortex typical of a selective serotonin reuptake inhibitor. The maximal response produced by (+)-12a was similar to that of fluoxetine but at an approximately 10-fold lower dose.
Assuntos
Ciclopropanos/síntese química , Indóis/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Triptaminas/síntese química , Animais , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/farmacologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Humanos , Indóis/química , Indóis/farmacologia , Microdiálise , Modelos Moleculares , Conformação Molecular , Ensaio Radioligante , Ratos , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Triptaminas/química , Triptaminas/farmacologiaRESUMO
A series of conformationally restricted homotryptamines has been synthesized and shown to be potent inhibitors of hSERT. Conformational restriction of the homotryptamine side chain was attained by the insertion of a cyclopentyl ring, with the indole ring and the terminal dialkylamino group occupying the 1- and 3-positions, respectively. Nitrile and fluoro substitutions at the indole 5-position gave highest hSERT potency. Preferred cyclopentane ring stereochemistry in both series was cis (1S,3R for 5-CN compound 8a, 1R,3S for 5-F compound 9a). High hSERT binding affinity was observed for 8a and 9a (0.22 and 0.63 nM, respectively). The corresponding trans isomers were 4-9 times less potent. 8a, dosed at 1 and 3 mg/kg po, produced a robust, dose-dependent increase in extracellular serotonin in the frontal cortex of rats, similar to that induced by paroxetine at 5 mg/kg, po. By contrast, 9a did not produce a significant increase in extracellular serotonin in rat frontal cortex at 3 mg/kg po due to relatively low brain and plasma levels.
Assuntos
Ciclopentanos/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Triptaminas/síntese química , Animais , Disponibilidade Biológica , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Ciclopentanos/química , Ciclopentanos/farmacologia , Espaço Extracelular/metabolismo , Humanos , Microdiálise , Modelos Moleculares , Conformação Molecular , Ratos , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-Atividade , Triptaminas/química , Triptaminas/farmacologiaRESUMO
Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.
Assuntos
Pirazinas/química , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Humanos , Macaca fascicularis , Masculino , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose-response similar to the SSRI fluoxetine in microdialysis studies in rats.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Triptaminas/química , Animais , Cicloexenos/síntese química , Cicloexenos/química , Cicloexenos/farmacologia , Fluoxetina/química , Fluoxetina/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Microdiálise , Conformação Molecular , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Ratos , Inibidores Seletivos de Recaptação de Serotonina/síntese químicaRESUMO
A series of hybrid molecules containing the cyclopropylmethylamino side chain found in homotryptamine (1S,2S)-2c and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for the human serotonin transporter determined. The most potent isosteres were CN-substituted naphthalenes. These results demonstrate that isosteric aromatic cores which lack an H-bond donor site may be substituted for the indole nucleus without substantial loss in hSERT binding.
Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Triptaminas/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Compostos Heterocíclicos/síntese química , Humanos , Concentração Inibidora 50 , Conformação Molecular , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Relação Estrutura-AtividadeRESUMO
A series of novel 5,5-diphenylimidazolones was synthesized and evaluated for activity against the human neuropeptide Y5 receptor. The 3-pyridyl analog 46 demonstrated an IC(50) of 8.3 nM with a favorable pharmacokinetic profile in rats, but was ineffective in reducing food intake.
Assuntos
Fármacos Antiobesidade/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Imidazóis/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Animais , Fármacos Antiobesidade/síntese química , Humanos , Imidazóis/síntese química , Concentração Inibidora 50 , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeo Y/metabolismo , Relação Estrutura-Atividade , Fatores de TempoRESUMO
A series of N,N-dimethylhomotryptamines was prepared and their binding affinities at the serotonin transporter (SERT) were determined. Compounds possessing an electron withdrawing substituent at the C5-position of the indole nucleus were found to be potent SSRIs. Initial attempts at conformational restriction of the propylamine sidechain by incorporation of a quinuclidine bicyclic structure did not improve binding affinity at SERT.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Triptaminas/química , Triptaminas/farmacologia , Linhagem Celular , Humanos , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Modelos Químicos , Estrutura Molecular , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
The synthesis of novel ligands for the NPY(2) receptor using solid phase split pool methodology is described. One of the analogues, diamine 16, was found to be a potent NPY(2) binder.
Assuntos
Diaminas/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Acilação , Linhagem Celular Tumoral , Diaminas/síntese química , Humanos , Concentração Inibidora 50 , Ligantes , Neuroblastoma/metabolismo , Ensaio Radioligante , Relação Estrutura-AtividadeRESUMO
4-Amino-N-arylpiperidines serve as effective bioisosteres for N-arylpiperazines in the series of dihydropyridine NPY1 receptor antagonists. These were prepared by a ZnCl2-mediated reductive amination reaction between elaborated primary amines, 2 or 5, and 4-arylpiperidones.
Assuntos
Materiais Biomiméticos/farmacocinética , Di-Hidropiridinas/química , Piperazinas/química , Piperidinas/farmacocinética , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Cloretos/química , Avaliação Pré-Clínica de Medicamentos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Relação Estrutura-Atividade , Compostos de Zinco/químicaRESUMO
Dihydropyridine 5a was found to be an inhibitor of neuropeptide Y(1) binding in a high throughput (125)I-PYY screening assay. Structure-activity studies around certain portions of the dihydropyridine chemotype identified BMS-193885 (6e) as a potent and selective Y(1) receptor antagonist. In a forskolin-stimulated c-AMP production assay using CHO cells expressing the human Y(1) receptor, 6e demonstrated full functional antagonism (K(b)=4.5 nM). Compound 6e inhibited NPY-induced feeding in satiated rats when dosed at 3.0 and 10.0 mg/kg (ip), and also decreased spontaneous overnight food consumption in rats at doses of 10 and 20 mg/kg (ip).