RESUMO
A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.
Assuntos
Química Farmacêutica/métodos , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Norepinefrina/antagonistas & inibidores , Propanolaminas/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores da Captação Adrenérgica/farmacologia , Animais , Cães , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Químicos , Propanolaminas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as monoamine reuptake inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter.
Assuntos
Inibidores da Captação Adrenérgica/química , Indóis/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/farmacocinética , Animais , Humanos , Indóis/síntese química , Indóis/farmacocinética , Modelos Animais , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ratos , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The discovery of a series of 4-aminoethyl-3-(phenylsulfonyl)-1H-indoles, dual acting norepinephrine reuptake inhibitors (NRIs) and 5-HT(2A) receptor antagonists, is described. The synthesis and structure-activity relationship (SAR) of this novel series of compounds is also presented.
Assuntos
Indóis/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Humanos , Indóis/síntese química , Indóis/metabolismo , Inibidores da Captação de Neurotransmissores/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas da Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/antagonistas & inibidores , Benzimidazóis/química , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/química , Norepinefrina/metabolismo , EstereoisomerismoRESUMO
Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.
Assuntos
Indóis/síntese química , Indóis/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/antagonistas & inibidores , Humanos , Indóis/química , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Progesterone (P4) is an essential reproductive steroid hormone required for many aspects of female reproductive physiology. Progestins are compounds that demonstrate progesterone-like activity and are used in oral contraception, hormone therapy, and treatment of some reproductive disorders, but differ widely in their chemical structures, potency, and pharmacokinetics. While numerous studies have assessed progestins on specific endpoints, little is known about the activation of global gene expression by progestins. We used Affymetrix GeneChip U133A expression arrays to examine the action of P4 and six clinically relevant synthetic progestins (3-ketodesogestrel, drospirenone, levonorgestrel, medroxyprogesterone acetate, norethindrone acetate, and trimegestone) on the progesterone receptor (PR)-positive T47Dco and the PR-negative T47D-Y breast cancer cell lines. Excluding drospirenone, one or more of the progestins-regulated 329 genes, with 30 genes regulated by at least 2.0-fold by all progestins in the T47Dco cells. The synthetic progestins show a high degree of similarity in their transcriptional responses, and each progestin regulates between 77 and 91% of the genes regulated by P4. Independent quantitative RT-PCR analysis confirmed a similar regulation for S100P, PPL, IL20RA, NET1, ATP1A1, HIG2, and CXCL12 (SDF-1) by all seven progestins. Attempts to find differentially regulated genes by any progestin compared to all other treatments failed, suggesting any differences are quantitative, not qualitative. This analysis demonstrates a high degree of similarity among these progestins on PR-regulated gene expression in T47D cells, suggesting a similar and fairly specific mode of action.
Assuntos
Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Progesterona/metabolismo , Receptores de Progesterona/metabolismo , Fosfatase Alcalina/metabolismo , Androstenos/química , Linhagem Celular Tumoral , Análise por Conglomerados , Desogestrel/química , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica , Humanos , Levanogestrel/química , Ligantes , Acetato de Medroxiprogesterona/química , Análise de Sequência com Séries de Oligonucleotídeos , Progesterona/química , Progestinas/química , Promegestona/análogos & derivados , Promegestona/química , RNA/metabolismo , Receptores de Estrogênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição GênicaRESUMO
Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.
Assuntos
Analgésicos/síntese química , Benzotiazóis/síntese química , Óxidos S-Cíclicos/síntese química , Morfolinas/síntese química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Tiadiazóis/síntese química , Dor Aguda/tratamento farmacológico , Administração Oral , Analgésicos/química , Analgésicos/farmacologia , Animais , Benzotiazóis/química , Benzotiazóis/farmacologia , Disponibilidade Biológica , Linhagem Celular , Dor Crônica/tratamento farmacológico , Cricetinae , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacologia , Cães , Humanos , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Injeções Intravenosas , Masculino , Morfolinas/química , Morfolinas/farmacologia , Neuralgia/tratamento farmacológico , Ratos , Estereoisomerismo , Tiadiazóis/química , Tiadiazóis/farmacologiaRESUMO
The potency and selectivity of a series of 1-{(1S)-2-[amino]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol analogues are described. These compounds were prepared to improve in vitro metabolic stability and achieve brain penetration. Compound 13 (WAY-260022, NRI-022) was found to be a potent inhibitor of norepinephrine reuptake and demonstrated excellent selectivity over the serotonin and dopamine transporters. Additionally, 13 exhibited oral efficacy in a rat model of thermoregulatory dysfunction.
RESUMO
Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC(50) = 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.
Assuntos
Indóis/farmacologia , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Propanolaminas/farmacologia , Animais , Regulação da Temperatura Corporal/efeitos dos fármacos , Feminino , Indóis/síntese química , Indóis/química , Espectroscopia de Ressonância Magnética , Inibidores da Captação de Neurotransmissores/síntese química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Dor/tratamento farmacológico , Propanolaminas/síntese química , Propanolaminas/química , Ratos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Structural modification of a virtual screening hit led to the identification of a new series of 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols which are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound S-17b (WYE-103231) had low nanomolar hNET potency (IC(50) = 1.2 nM) and excellent selectivity for hNET over hSERT (>1600-fold) and hDAT (>600-fold). S-17b additionally had a good pharmacokinetic profile and demonstrated oral efficacy in rat models of ovariectomized-induced thermoregulatory dysfunction and morphine dependent flush as well as the hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain.
Assuntos
Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacologia , Descoberta de Drogas/métodos , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Tiadiazóis/química , Tiadiazóis/farmacologia , Animais , Linhagem Celular , Óxidos S-Cíclicos/síntese química , Óxidos S-Cíclicos/farmacocinética , Feminino , Humanos , Masculino , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacocinética , Ratos , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/farmacocinéticaRESUMO
Sequential structural modifications of the aryloxypropanamine template (e.g., atomoxetine, 2) led to a novel series of 1-(3-amino-2-hydroxy-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors (NRIs). In general, this series of compounds potently blocked the human norepinephrine transporter (hNET) while exhibiting selectivity at hNET against both the human serotonin (hSERT) and dopamine transporters (hDAT). Numerous compounds (e.g., 19-22) had low nonamolar hNET potency with IC(50) values of 7-10 nM and excellent selectivity (>500 fold) at hNET over hSERT and hDAT. Several compounds, such as 20 and 22, were tested in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction and were efficacious at oral doses of 3 mg/kg in reducing the tail skin temperature. In addition, compound 20 was also studied in the rat hot plate and spinal nerve ligation (SNL) models of acute and neuropathic pain, respectively, and was orally efficacious at doses of 3-10 mg/kg.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Administração Oral , Animais , Comportamento Animal/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Transporte Biológico/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Feminino , Humanos , Hiperalgesia/fisiopatologia , Masculino , Inibidores da Captação de Neurotransmissores/administração & dosagem , Inibidores da Captação de Neurotransmissores/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Propanolaminas/química , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Nervos Espinhais/efeitos dos fármacos , Nervos Espinhais/fisiologia , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.
Assuntos
Cicloexanóis/química , Etilaminas/química , Etilaminas/farmacologia , Norepinefrina/metabolismo , Simportadores/antagonistas & inibidores , Animais , Linhagem Celular , Etilaminas/uso terapêutico , Feminino , Humanos , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Dor/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Simportadores/metabolismoRESUMO
The purpose of this study was to characterize a new chemical entity, desvenlafaxine succinate (DVS). DVS is a novel salt form of the isolated major active metabolite of venlafaxine. Competitive radioligand binding assays were performed using cells expressing either the human serotonin (5-HT) transporter (hSERT) or norepinephrine (NE) transporter (hNET) with K(i) values for DVS of 40.2 +/- 1.6 and 558.4 +/- 121.6 nM, respectively. DVS showed weak binding affinity (62% inhibition at 100 microM) at the human dopamine (DA) transporter. Inhibition of [3H]5-HT or [3H]NE uptake by DVS for the hSERT or hNET produced IC50 values of 47.3 +/- 19.4 and 531.3 +/- 113.0 nM, respectively. DVS (10 microM), examined at a large number of nontransporter targets, showed no significant activity. DVS (30 mg/kg orally) rapidly penetrated the male rat brain and hypothalamus. DVS (30 mg/kg orally) significantly increased extracellular NE levels compared with baseline in the male rat hypothalamus but had no effect on DA levels using microdialysis. To mimic chronic selective serotonin reuptake inhibitor treatment and to block the inhibitory 5-HT(1A) autoreceptors, a 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo hexanecarboxamide maleate salt (WAY-100635) (0.3 mg/kg s.c.), was administered with DVS (30 mg/kg orally). 5-HT increased 78% compared with baseline with no additional increase in NE or DA levels. In conclusion, DVS is a new 5-HT and NE reuptake inhibitor in vitro and in vivo that demonstrates good brain-to-plasma ratios, suggesting utility in a variety of central nervous system-related disorders.