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
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
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
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
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
A series of 4'-hydroxyphenyl-aryl-carbaldehyde oximes (5b) was prepared and found to have high affinity (4nM) and modest selectivity (39-fold) for estrogen receptor-beta (ERbeta). Substitution of one of the core rings of the scaffold based around these novel ligands further expanded our knowledge in the quest toward achieving high affinity and selectivity for ERbeta. An X-ray co-crystal of structure 11 revealed that the oxime moiety was mimicking the C-ring of genistein, as previously predicted by SAR and docking studies.
Assuntos
Aldeídos/síntese química , Aldeídos/farmacologia , Receptor beta de Estrogênio/efeitos dos fármacos , Oximas/síntese química , Oximas/farmacologia , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Cristalografia por Raios X , Humanos , Indicadores e Reagentes , Ligantes , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
A new class of estrogen receptor beta (ERbeta) ligands based on the 2-phenylquinoline scaffold was prepared. Several analogues with C4 substitution displayed high affinity (3-5 nM) and significant selectivity (up to 83-fold) for ERbeta. The best compound, 13b, was profiled as a selective partial agonist for ERbeta at 1 muM in a cell-based transcriptional assay. Uterine weight bioassay of 13b indicated no activation of ERalpha in vivo.