RESUMEN
5-Aryl-4-carboxamide-1,3-oxazoles are a novel, potent and selective series of GSK-3 inhibitors. The optimization of the series to yield compounds with cell activity and brain permeability is described.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Oxazoles/química , Oxazoles/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Animales , Trastorno Bipolar/tratamiento farmacológico , Encéfalo/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Modelos Moleculares , Oxazoles/síntesis química , Oxazoles/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The discovery of a novel series of 2-(4-pyridyl)thienopyridinone GSK-3ß inhibitors is reported. X-ray crystallography reveals its binding mode and enables rationalization of the SAR. The initial optimization of the template for improved cellular activity and predicted CNS penetration is also presented.
Asunto(s)
Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/farmacología , Tiofenos/farmacología , Línea Celular , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Glucógeno Sintasa Quinasa 3 beta , Humanos , Modelos Moleculares , Estructura Molecular , Permeabilidad/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridonas/síntesis química , Piridonas/química , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
In an effort to identify selective drug like pan-antagonists of the 5-HT1 autoreceptors, studies were conducted to elaborate a previously reported dual acting 5-HT1 antagonist/SSRI structure. A novel series of compounds was identified showing low intrinsic activities and potent affinities across the 5-HT1A, 5-HT1B, and 5-HT1D receptors as well as high selectivity against the serotonin transporter. From among these compounds, 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (36) was found to combine potent in vivo activity with a strong preclinical developability profile, and on this basis it was selected as a drug candidate with the aim of assessing its potential as a fast-onset antidepressant/anxiolytic.
Asunto(s)
Imidazoles/farmacología , Quinolinas/farmacología , Antagonistas de la Serotonina/farmacología , Administración Oral , Animales , Células CHO , Cromatografía Liquida , Cricetulus , Descubrimiento de Drogas , Humanos , Imidazoles/administración & dosificación , Imidazoles/química , Espectroscopía de Resonancia Magnética , Masculino , Quinolinas/administración & dosificación , Quinolinas/química , Ratas Sprague-Dawley , Receptores de Serotonina/clasificación , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/química , Espectrometría de Masas en TándemRESUMEN
A new class of selective NPS antagonist was developed starting from a commercially available product identified by screening activities. Experimental NMR observations and computational experiments allowed the discovery of a new class of derivatives. 5-Phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one represents a new lead compound in the NPS antagonist field.
Asunto(s)
Compuestos de Azabiciclo/química , Imidazoles/química , Neuropéptidos/antagonistas & inhibidores , Piperidinas/química , Animales , Simulación por Computador , Diseño de Fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Microsomas Hepáticos/metabolismo , Neuropéptidos/metabolismo , Ratas , TermodinámicaRESUMEN
Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Antagonistas de los Receptores Histamínicos H1/síntesis química , Hipnóticos y Sedantes/síntesis química , Receptor de Serotonina 5-HT2A/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/síntesis química , Sueño/efectos de los fármacos , Compuestos de Espiro/síntesis química , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Línea Celular , Corteza Cerebral/metabolismo , Cricetinae , Cricetulus , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Masculino , Microsomas Hepáticos/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT2/química , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-ActividadAsunto(s)
Dibenzocicloheptenos/síntesis química , Dibenzocicloheptenos/farmacología , Hipnóticos y Sedantes/síntesis química , Ciclización , Dibenzocicloheptenos/química , Humanos , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Mianserina/análogos & derivados , Mianserina/química , Mianserina/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3mg/kg po.
Asunto(s)
Carbamatos/química , Carbamatos/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Animales , Carbamatos/metabolismo , Carbamatos/farmacocinética , Línea Celular , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Microsomas Hepáticos/metabolismo , Ratas , Compuestos de Espiro/metabolismo , Compuestos de Espiro/farmacocinética , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To evaluate the intraocular pressure (IOP) lowering efficacy and safety of travoprost 0.004% in patients with open-angle glaucoma or ocular hypertension, poorly controlled with or intolerance to beta-blockers. To record the short-term effect on diastolic ocular perfusion pressure (DOPP). RESEARCH DESIGN AND METHODS: One hundred and three patients with open-angle glaucoma or ocular hypertension were treated with travoprost 0.004% once daily for 90 days in an open-label, non-controlled study. Efficacy and safety were assessed at baseline, after 45 and 90 days. Clinical registry number IT0301. MAIN OUTCOME MEASURES: The primary outcome measure, IOP, was recorded at 10 am, 12 pm, and 4 pm at each visit. DOPP was evaluated at 10 am, at baseline and visit 3. Safety measures included adverse events, biomicroscopy, visual acuity, heart rate, and blood pressure. RESULTS: Mean IOP was reduced from 22.2 +/- 1.7 mmHg to 16.5 +/- 2.1 after 45 days (p < 0.0001), and to 16.1 +/- 2.2 after 90 days (p < 0.0001). The DOPP increased by 5.3 +/- 6.3 mmHg after 90 days of treatment (p < 0.0001). No drug related serious adverse events were reported during the study. CONCLUSIONS: The open-label and non-comparative nature of the study represented its principal limitations. The study confirmed the efficacy and tolerability of travoprost in the treatment of open-angle glaucoma or ocular hypertension, in a subset of patients unsuccessfully treated with beta-blockers. In this study, travoprost significantly increased DOPP at short-term follow-up. Further studies to assess the effect of travoprost on DOPP are warranted.
Asunto(s)
Cloprostenol/análogos & derivados , Glaucoma de Ángulo Abierto/tratamiento farmacológico , Hipertensión Ocular/tratamiento farmacológico , Anciano , Cloprostenol/administración & dosificación , Cloprostenol/farmacología , Cloprostenol/uso terapéutico , Femenino , Glaucoma de Ángulo Abierto/fisiopatología , Humanos , Presión Intraocular/efectos de los fármacos , Masculino , Persona de Mediana Edad , Hipertensión Ocular/fisiopatología , Estudios Prospectivos , Travoprost , Resultado del TratamientoRESUMEN
Novel 2-methyl-5-quinolinyl-1-piperazinylalkyl-3,4-dihydro-2H-1,4-benzoxazin-3-ones showing high affinities for the 5-HT(1A/1B/1D) receptors coupled with potent 5-HT reuptake inhibitory activity have been discovered. This is the first report describing docking of the lead compound 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2H-1,4-benzoxazin-3(4H)-one 1, into a model of the 5-HT transporter and the 5-HT(1A) receptor model.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Administración Oral , Animales , Cromatografía/métodos , Diseño de Fármacos , Humanos , Cinética , Masculino , Modelos Químicos , Conformación Molecular , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Investigation of a series 6-[2-(4-aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones has led to the discovery of potent 5-HT(1A/1B/1D) receptor antagonists with and without additional SerT affinity. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.
Asunto(s)
Benzoxazoles/síntesis química , Piperazinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/farmacología , Benzoxazoles/farmacología , Diseño de Fármacos , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Modelos Químicos , Piperazina , Piperazinas/química , Piperazinas/farmacología , Ratas , Antagonistas del Receptor de Serotonina 5-HT1RESUMEN
The synthesis and the structure activity of a new series of pyrrolo[1,2-a]pyrazine is reported. These molecules are potent and selective non-competitive mGluR5 antagonists and may shed new light on the pattern of substitution tolerated by this receptor.
Asunto(s)
Pirazinas/farmacología , Pirroles/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Fluorescencia , Humanos , Estructura Molecular , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Pirazinas/síntesis química , Pirroles/síntesis química , Receptor del Glutamato Metabotropico 5 , Relación Estructura-ActividadRESUMEN
One of the still unresolved problems in parallel synthesis is the availability of a general and rapid method for the transformation of a primary amine into the corresponding secondary amine without the issue of polyalkylation. Following the Fukuyama method, which is based on the alkylation of o-nitrobenzenesulfonamides, followed by removal of the sulfonyl group, we have developed a simple protocol which can be easily applied to parallel synthesis making use of supported reagents and scavengers. To verify the robustness of the method, a small representative array of secondary amines have been prepared. Moreover, taking advantage of the possibility to use different supported reagents in the same pot, we also prepared, starting from primary amines, a series of differently substituted tertiary amines.