RESUMEN
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.
Asunto(s)
Catálisis , Química Clic , Cobre/química , Oligonucleótidos/química , Azidas/química , Estructura Molecular , EstereoisomerismoRESUMEN
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.
Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Diseño de Fármacos , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Piridinas/síntesis química , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/síntesis química , Inhibidores de Captación Adrenérgica/metabolismo , Inhibidores de Captación Adrenérgica/farmacología , Línea Celular , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos/métodos , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Fenoles/síntesis química , Fenoles/metabolismo , Fenoles/farmacología , Piridinas/metabolismo , Piridinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Agonistas de Receptores de Serotonina/metabolismo , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
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.
Asunto(s)
Descubrimiento de Drogas , Éteres/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Piperazinas/farmacología , Piperidinas/farmacología , Agonistas del Receptor de Serotonina 5-HT1 , Dopamina/metabolismo , Éteres/síntesis química , Éteres/química , Estructura Molecular , Inhibidores de la Captación de Neurotransmisores/síntesis química , Inhibidores de la Captación de Neurotransmisores/química , Piperazinas/síntesis química , Piperazinas/química , Piperidinas/síntesis química , Piperidinas/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Indoles/síntesis química , Indoles/farmacología , Microsomas Hepáticos/efectos de los fármacos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/farmacología , Buspirona/farmacología , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Indoles/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pirimidinas/química , Agonistas de Receptores de Serotonina/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Inhibidores de Captación Adrenérgica/síntesis química , Química Farmacéutica/métodos , Morfolinas/síntesis química , Norepinefrina/antagonistas & inhibidores , Inhibidores de Captación Adrenérgica/farmacología , Fármacos del Sistema Nervioso Central/química , Diseño de Fármacos , Humanos , Cetonas/química , Modelos Químicos , Morfolinas/química , Morfolinas/farmacología , Norepinefrina/química , Reboxetina , Estereoisomerismo , Relación Estructura-Actividad , Tolueno/químicaRESUMEN
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.
Asunto(s)
Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Sistema Nervioso Central/efectos de los fármacos , Técnicas Químicas Combinatorias , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pirrolidinas/química , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/química , EstereoisomerismoRESUMEN
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.
Asunto(s)
Amidas/síntesis química , Compuestos Aza/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Fármacos Neuroprotectores/síntesis química , Proteína 1A de Unión a Tacrolimus/antagonistas & inhibidores , Proteína 1A de Unión a Tacrolimus/química , Amidas/química , Compuestos Aza/química , Sitios de Unión , Compuestos Heterocíclicos de 4 o más Anillos/química , Enlace de Hidrógeno , Isoquinolinas/síntesis química , Isoquinolinas/química , Ligandos , Fármacos Neuroprotectores/química , Relación Estructura-Actividad , Tacrolimus/químicaRESUMEN
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.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacocinética , Dopamina/metabolismo , Agonismo Parcial de Drogas , Modelos Biológicos , Norepinefrina/antagonistas & inhibidores , Corteza Prefrontal/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacocinética , Animales , Clorhidrato de Atomoxetina , Buspirona/farmacocinética , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Norepinefrina/metabolismo , Corteza Prefrontal/efectos de los fármacos , Propilaminas/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
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.