RESUMO
Copper-free click chemistry between cyclooctynes and azide is a mild, fast and selective technology for conjugation of oligonucleotides. However, technology for site-specific introduction of the requisite probes by automated protocols is scarce, while the reported cyclooctynes are large and hydrophobic. In this work, it is demonstrated that the introduction of bicyclo[6.1.0]nonyne (BCN) into synthetic oligonucleotides is feasible by standard solid-phase phosphoramidite chemistry. A range of phosphoramidite building blocks is presented for incoporation of BCN or azide, either on-support or in solution. The usefulness of the approach is demonstrated by the straightforward and high-yielding conjugation of the resulting oligonucleotides, including biotinylation, fluorescent labeling, dimerization and attachment to polymer.
Assuntos
Catálise , Química Click , Cobre/química , Oligonucleotídeos/química , Azidas/química , Estrutura Molecular , EstereoisomerismoRESUMO
Evidence suggests that compounds possessing both norepinephrine reuptake inhibition and 5-HT(1A) partial agonism (NRI/5-HT(1A)) activities may have a greater efficacy in treating neuropsychiatric disorders than compounds possessing either activity alone. The objectives of the present study were first to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of the plasma concentrations of atomoxetine (NRI) and buspirone (5-HT(1A) partial agonist), administered alone and in combination, on the prefrontal cortex dopamine levels in rats, and second to use the model developed to characterize the PK/PD relationship of novel NRI/5-HT(1A) compounds, PF-04269339 and PF-03529936, in a NRI/5-HT(1A) drug discovery program. Maximal dopamine elevation was twofold higher after administration of atomoxetine and buspirone in combination, PF-04269339, or PF-03529936 than after administration of atomoxetine or buspirone alone. A mechanism-based extended indirect response model characterized the time profiles of the prefrontal cortex dopamine response to atomoxetine and buspirone, administered alone or in combination. After fixing three mechanism-specific pharmacodynamic parameters (I (max) and γ2 for NRI and γ1 for 5-HT(1A)) based on the model for atomoxetine and/or buspirone, the model fitted the exposure-response profiles of PF-04269339 and PF-03529936 well. Good in vitro-to-in vivo correlation was demonstrated with the compound-specific pharmacodynamic parameters (IC(50) for NRI and SC(50) and S (max) for 5-HT(1A)) across the compounds. In summary, a piecewise modeling approach was used successfully for the characterization of the PK/PD relationship of novel NRI/5-HT(1A) compounds on prefrontal cortex dopamine levels in rats. The application and value of the mechanism-based modeling in the dual pharmacology drug discovery program are also discussed.
Assuntos
Inibidores da Captação Adrenérgica/farmacocinética , Dopamina/metabolismo , Agonismo Parcial de Drogas , Modelos Biológicos , Norepinefrina/antagonistas & inibidores , Córtex Pré-Frontal/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacocinética , Animais , Cloridrato de Atomoxetina , Buspirona/farmacocinética , Relação Dose-Resposta a Droga , Humanos , Masculino , Norepinefrina/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Propilaminas/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
Preclinical studies suggest that compounds with dual norepinephrine reuptake inhibitor (NRI) and 5-HT(1A) partial agonist properties may provide an important new therapeutic approach to ADHD, depression, and anxiety. Reported herein is the discovery of a novel chemical series with a favorable NRI and 5-HT(1A) partial agonist pharmacological profile as well as excellent selectivity for the norepinephrine transporter over the dopamine transporter.
Assuntos
Inibidores da Captação Adrenérgica/síntese química , Desenho de Fármacos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Piridinas/síntese química , Agonistas do Receptor 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/síntese química , Inibidores da Captação Adrenérgica/metabolismo , Inibidores da Captação Adrenérgica/farmacologia , Linhagem Celular , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Fenóis/síntese química , Fenóis/metabolismo , Fenóis/farmacologia , Piridinas/metabolismo , Piridinas/farmacologia , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Compounds that are both norepinephrine reuptake inhibitors (NRI) and 5-HT1(A) partial agonists may have the potential to treat neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and depression. Targeted screening of NRI-active compounds for binding to the 5-HT(1A) receptor provided a series of thiomorpholinone hits with this dual activity profile. Several iterations of design, synthesis, and testing led to substituted piperidine diphenyl ethers which are potent NRIs with 5-HT1(A) partial agonist properties. In addition, optimization of these molecules provided compounds which exhibit selectivity for NRI over the dopamine (DAT) and serotonin (SERT) reuptake transporters. Monoamine and 5-HT(1A) in vitro functional activities for select compounds from the developed piperidine diphenyl ether series are also presented.
Assuntos
Descoberta de Drogas , Éteres/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina , Dopamina/metabolismo , Éteres/síntese química , Éteres/química , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/química , Piperazinas/síntese química , Piperazinas/química , Piperidinas/síntese química , Piperidinas/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Aminopyrimidine 2 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-cyclopropylpyrimidin-2-amine) emerged from a high throughput screen as a novel 5-HT(1A) agonist. This compound showed moderate potency for 5-HT(1A) in binding and functional assays, as well as moderate metabolic stability. Implementation of a strategy for improving metabolic stability by lowering the lipophilicity (cLogD) led to identification of methyl ether 31 (4-(1-(2-(1H-indol-3-yl)ethyl)piperidin-3-yl)-N-(2-methoxyethyl)pyrimidin-2-amine) as a substantially improved compound within the series.
Assuntos
Indóis/síntese química , Indóis/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/farmacologia , Buspirona/farmacologia , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Indóis/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirimidinas/química , Agonistas do Receptor de Serotonina/química , Relação Estrutura-AtividadeRESUMO
As part of a discovery effort aimed at identifying novel norepinephrine reuptake inhibitors (NRIs), a number of substituted morpholines were designed and synthesized. The target compounds contain vicinal stereogenic centers, and the program was greatly facilitated by the adoption of efficient synthetic routes which allowed for the late stage incorporation of structural and physicochemical diversity into the targets. Structure-activity relationships were developed by optimizing individual ring components of the structure for NRI potency and for selectivity against other monoamine reuptake transporters. Several novel morpholine derivatives with a potent and selective NRI profile are described.
Assuntos
Inibidores da Captação Adrenérgica/síntese química , Química Farmacêutica/métodos , Morfolinas/síntese química , Norepinefrina/antagonistas & inibidores , Inibidores da Captação Adrenérgica/farmacologia , Fármacos do Sistema Nervoso Central/química , Desenho de Fármacos , Humanos , Cetonas/química , Modelos Químicos , Morfolinas/química , Morfolinas/farmacologia , Norepinefrina/química , Reboxetina , Estereoisomerismo , Relação Estrutura-Atividade , Tolueno/químicaRESUMO
Derivatives of (3S)-N-(biphenyl-2-ylmethyl)pyrrolidin-3-amine are disclosed as a new series of noradrenaline reuptake inhibitors (NRI). Carboxamide 9e, carbamate 11b and sulfonamide 13a were identified as potent NRIs with excellent selectivity over SRI and DRI, good in vitro metabolic stability and weak CYP inhibition. Carbamate 11b demonstrated superior transit performance in MDCK-mdr1 cell lines with minimal P-gp efflux which was attributed to reduced HBA capacity of the carbamate group. Evaluation in vivo, in rat microdialysis experiments, showed 11b increased noradrenaline levels by 400% confirming good CNS penetration.
Assuntos
Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Sistema Nervoso Central/efeitos dos fármacos , Técnicas de Química Combinatória , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Pirrolidinas/química , Ratos , Inibidores Seletivos de Recaptação de Serotonina/química , EstereoisomerismoRESUMO
Several beta-amino tetrazole analogs of gabapentin 1 and pregabalin 2 were prepared by one of two convergent, highly efficient routes, and their affinity for the alpha(2)-delta protein examined. Two select compounds with potent affinity for alpha(2)-delta, 8a and 16a, were subsequently tested in vivo in an audiogenic seizure model and found to elicit protective effects.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Ácidos Carboxílicos/química , Epilepsia Reflexa/prevenção & controle , Ácido gama-Aminobutírico/análogos & derivados , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Animais , Anticonvulsivantes/química , Sítios de Ligação , Ácidos Cicloexanocarboxílicos/síntese química , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Gabapentina , Camundongos , Camundongos Endogâmicos DBA , Estrutura Molecular , Pregabalina , Subunidades Proteicas/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Ácido gama-Aminobutírico/síntese química , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/farmacologiaRESUMO
Since the discovery that FK-506 promotes neurite outgrowth, considerable attention has been focused on the development of potent nonimmunosuppressive ligands for FK-506 binding proteins (FKBPs). Such neuroimmunophilin agents have been reported to show neuroregenerative activity in a variety of cell and animal models including neurite outgrowth, age-related cognitive decline, Parkinson's disease, peripheral nerve injury, optic nerve degeneration, and diabetic neuropathy. We have designed and synthesized a unique series of tetracyclic aza-amides that have been shown to be potent FKBP12 rotamase inhibitors. The structure-activity relationships established in this study have demonstrated diverse structural modifications that result in potent rotamase inhibitory activity.