RESUMO
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 5-arylamino-1,2,4-triazin-6(1H)-ones was synthesized and evaluated as antagonists at the corticotropin releasing factor receptor. Formation of CYP-mediated oxidative reactive metabolites previously observed in a related N(3)-phenylpyrazinone structure was minimized by incorporation of the additional ring nitrogen found in the triazinones.
Assuntos
Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Triazinas/síntese química , Triazinas/farmacologia , Animais , Humanos , Concentração Inibidora 50 , Oxirredução , Pirazinas , Ratos , Relação Estrutura-AtividadeRESUMO
Detailed metabolic characterization of 8, an earlier lead pyrazinone-based corticotropin-releasing factor-1 (CRF(1)) receptor antagonist, revealed that this compound formed significant levels of reactive metabolites, as measured by in vivo and in vitro biotransformation studies. This was of particular concern due to the body of evidence suggesting that reactive metabolites may be involved in idiosyncratic drug reactions. Further optimization of the structure-activity relationships and in vivo properties of pyrazinone-based CRF(1) receptor antagonists and studies to assess the formation of reactive metabolites led to the discovery of 19e, a high affinity CRF(1) receptor antagonist (IC(50) = 0.86 nM) wherein GSH adducts were estimated to be only 0.1% of the total amount of drug-related material excreted through bile and urine, indicating low levels of reactive metabolite formation in vivo. A novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group in 19e contributed to the potency and improved in vivo properties of this compound and related analogues. 19e had excellent pharmacokinetic properties in rats and dogs and showed efficacy in the defensive withdrawal model of anxiety in rats. The lowest efficacious dose was 1.8 mg/kg. The results of a two-week rat safety study with 19e indicated that this compound was well-tolerated.
Assuntos
Pirazinas/metabolismo , Pirazinas/farmacologia , Piridinas/metabolismo , Piridinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Cães , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Masculino , Pirazinas/administração & dosagem , Pirazinas/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , RatosRESUMO
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
A series of pyrazinone-based heterocycles was identified as potent and orally active corticotropin-releasing factor-1 (CRF(1)) receptor antagonists. Selected compounds proved efficacious in an anxiety model in rats; however, pharmacokinetic properties were not optimal. In this article, we describe an in vitro intrinsic clearance-based approach to the optimization of pyrazinone-based CRF(1) receptor antagonists wherein sites of metabolism were identified by incubation with human liver microsomes. It was found that the rate of metabolism could be decreased by incorporation of appropriate substituents at the primary sites of metabolism. This led to the discovery of compound 12x, a highly potent (IC(50) = 1.0 nM) and selective CRF(1) receptor antagonist with good oral bioavailability (F = 52%) in rats and efficacy in the defensive withdrawal anxiety test in rats.
Assuntos
Pirazinas/farmacologia , Pirazinas/farmacocinética , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Humanos , Concentração Inibidora 50 , Masculino , Taxa de Depuração Metabólica , Pirazinas/química , Pirazinas/metabolismo , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismoRESUMO
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 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 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 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 present studies have identified a series of aminotriazines as novel 5-HT(7) receptor antagonists. Compounds 10 and 17 have high affinity for the 5-HT(7) receptor and do not bind to either the 5-HT(2C) or 5-HT(6) receptors. These compounds produce no agonist effects by themselves, and shift the dose-response curve of 5-CT to the right in the manner of an antagonist.