RESUMEN
A series of benzazepinones were synthesized and evaluated for block of Nav1.7 sodium channels. Compound 30 from this series displayed potent channel block, good selectivity versus other targets, and dose-dependent oral efficacy in a rat model of neuropathic pain.
Asunto(s)
Benzazepinas/farmacología , Neuralgia/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/farmacología , Animales , Modelos Animales de Enfermedad , RatasRESUMEN
Biological, genetic, and clinical evidence provide validation for N-type calcium channels (Ca(V)2.2) as therapeutic targets for chronic pain. A state-dependent Ca(V)2.2 inhibitor may provide an improved therapeutic window over ziconotide, the peptidyl Ca(V)2.2 inhibitor used clinically. Supporting this notion, we recently reported that in preclinical models, the state-dependent Ca(V)2 inhibitor (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1) has an improved therapeutic window compared with ziconotide. Here we characterize TROX-1 inhibition of Cav2.2 channels in more detail. When channels are biased toward open/inactivated states by depolarizing the membrane potential under voltage-clamp electrophysiology, TROX-1 inhibits Ca(V)2.2 channels with an IC(50) of 0.11 µM. The voltage dependence of Ca(V)2.2 inhibition was examined using automated electrophysiology. TROX-1 IC(50) values were 4.2, 0.90, and 0.36 µM at -110, -90, and -70 mV, respectively. TROX-1 displayed use-dependent inhibition of Ca(V)2.2 with a 10-fold IC(50) separation between first (27 µM) and last (2.7 µM) pulses in a train. In a fluorescence-based calcium influx assay, TROX-1 inhibited Ca(V)2.2 channels with an IC(50) of 9.5 µM under hyperpolarized conditions and 0.69 µM under depolarized conditions. Finally, TROX-1 potency was examined across the Ca(V)2 subfamily. Depolarized IC(50) values were 0.29, 0.19, and 0.28 µM by manual electrophysiology using matched conditions and 1.8, 0.69, and 1.1 µM by calcium influx for Ca(V)2.1, Ca(V)2.2, and Ca(V)2.3, respectively. Together, these in vitro data support the idea that a state-dependent, non-subtype-selective Ca(V)2 channel inhibitor can achieve an improved therapeutic window over the relatively state-independent Ca(V)2.2-selective inhibitor ziconotide in preclinical models of chronic pain.
Asunto(s)
Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo N/efectos de los fármacos , Indoles/química , Triazoles/química , Bloqueadores de los Canales de Calcio/farmacología , Línea Celular , Humanos , Indoles/farmacología , Concentración 50 Inhibidora , Potenciales de la Membrana/efectos de los fármacos , Técnicas de Placa-Clamp , Triazoles/farmacologíaRESUMEN
N-type calcium channels (Ca(v)2.2) have been shown to play a critical role in pain. A series of low molecular weight 2-aryl indoles were identified as potent Ca(v)2.2 blockers with good in vitro and in vivo potency.
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo N/metabolismo , Indoles/uso terapéutico , Dolor/tratamiento farmacológico , Animales , Bloqueadores de los Canales de Calcio/farmacocinética , Bloqueadores de los Canales de Calcio/farmacología , Perros , Haplorrinos , Humanos , Indoles/farmacocinética , Indoles/farmacología , RatasRESUMEN
INTRODUCTION: Student perceptions of active learning methods in medicinal chemistry education and correlation of those perceptions with academic performance measures have not been well studied. METHODS: Perceived usefulness of six active-learning activities (study guides, team activities, assignments/quizzes, make your own questions, and two types of in-class live polls) was evaluated by survey. Correlations between perceived usefulness, active-learning activity grade, course grade, first-time North American Pharmacist Licensure Examination (NAPLEX) score, and Pharmacy Curriculum Outcomes Assessment (PCOA) score were examined. RESULTS: Students perceived study guides as the most preferred activity while in-class live polls were least preferred. However, students agreed that all methods were useful to varying degrees. Although no significant correlation was seen between perceived utility of active-learning and course grades, positive correlations were observed between active-learning grades and NAPLEX (0.32), active-learning grades and PCOA (0.311), course grades and PCOA (0.449), and course grades and NAPLEX (0.483). Furthermore, correlation of PCOA and NAPLEX scores (0.456) was in line with previously published studies. CONCLUSIONS: Students found active-learning approaches to be useful to varying degrees. Active-learning activity and course grades had moderate, positive correlations with both NAPLEX and PCOA scores, suggesting that these active-learning activities may contribute to success on standardized exams.
Asunto(s)
Educación en Farmacia , Farmacia , Estudiantes de Farmacia , Química Farmacéutica , Curriculum , Evaluación Educacional , Humanos , América del Norte , Evaluación de Resultado en la Atención de Salud , Aprendizaje Basado en ProblemasRESUMEN
Voltage-gated calcium channel (Ca(v))2.2 (N-type calcium channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca(v)2.2 channels, is efficacious in treating refractory pain but exhibits a narrow therapeutic window and must be administered intrathecally. We have discovered an N-triazole oxindole, (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1), as a small-molecule, state-dependent blocker of Ca(v)2 channels, and we investigated the therapeutic advantages of this compound for analgesia. TROX-1 preferentially inhibited potassium-triggered calcium influx through recombinant Ca(v)2.2 channels under depolarized conditions (IC(50) = 0.27 microM) compared with hyperpolarized conditions (IC(50) > 20 microM). In rat dorsal root ganglion (DRG) neurons, TROX-1 inhibited omega-conotoxin GVIA-sensitive calcium currents (Ca(v)2.2 channel currents), with greater potency under depolarized conditions (IC(50) = 0.4 microM) than under hyperpolarized conditions (IC(50) = 2.6 microM), indicating state-dependent Ca(v)2.2 channel block of native as well as recombinant channels. TROX-1 fully blocked calcium influx mediated by a mixture of Ca(v)2 channels in calcium imaging experiments in rat DRG neurons, indicating additional block of all Ca(v)2 family channels. TROX-1 reversed inflammatory-induced hyperalgesia with maximal effects equivalent to nonsteroidal anti-inflammatory drugs, and it reversed nerve injury-induced allodynia to the same extent as pregabalin and duloxetine. In contrast, no significant reversal of hyperalgesia was observed in Ca(v)2.2 gene-deleted mice. Mild impairment of motor function in the Rotarod test and cardiovascular functions were observed at 20- to 40-fold higher plasma concentrations than required for analgesic activities. TROX-1 demonstrates that an orally available state-dependent Ca(v)2 channel blocker may achieve a therapeutic window suitable for the treatment of chronic pain.
Asunto(s)
Analgésicos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/fisiología , Indoles/farmacología , Triazoles/farmacología , Analgésicos/efectos adversos , Analgésicos/farmacocinética , Animales , Barorreflejo/efectos de los fármacos , Disponibilidad Biológica , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/farmacocinética , Canales de Calcio Tipo N/genética , Canales de Calcio Tipo R/fisiología , Proteínas de Transporte de Catión/fisiología , Línea Celular , Perros , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/fisiología , Hiperalgesia/tratamiento farmacológico , Hipotensión Ortostática/inducido químicamente , Indoles/efectos adversos , Indoles/farmacocinética , Masculino , Ratones , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/fisiología , Dolor/tratamiento farmacológico , Dolor/etiología , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Triazoles/efectos adversos , Triazoles/farmacocinéticaRESUMEN
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. A series of low molecular weight biaryl substituted pyrazole carboxamides were identified with good in-vitro potency and in-vivo efficacy. Compound 26, a Nav1.7 blocker has excellent efficacy in the Chung model of neuropathic pain.
Asunto(s)
Neuralgia/tratamiento farmacológico , Pirazoles/química , Pirazoles/uso terapéutico , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/metabolismo , Animales , Perros , Haplorrinos , Humanos , Microsomas Hepáticos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.7 , Pirazoles/farmacocinética , Pirazoles/farmacología , Ratas , Bloqueadores de los Canales de Sodio/farmacocinética , Bloqueadores de los Canales de Sodio/farmacología , Relación Estructura-ActividadRESUMEN
Voltage-gated sodium channels have been shown to play a critical role in neuropathic pain. With a goal to develop potent peripherally active sodium channel blockers, a series of low molecular weight biaryl substituted imidazoles, oxazoles, and thiazole carboxamides were identified with good in vitro and in vivo potency.
Asunto(s)
Neuralgia/tratamiento farmacológico , Oxazoles/uso terapéutico , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/metabolismo , Tiazoles/uso terapéutico , Animales , Perros , Humanos , Imidazoles/química , Imidazoles/metabolismo , Imidazoles/farmacología , Imidazoles/uso terapéutico , Microsomas Hepáticos/metabolismo , Canal de Sodio Activado por Voltaje NAV1.7 , Oxazoles/química , Oxazoles/metabolismo , Oxazoles/farmacología , Ratas , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Tiazoles/química , Tiazoles/metabolismo , Tiazoles/farmacologíaRESUMEN
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.
Asunto(s)
Compuestos de Bifenilo/química , Neuralgia/tratamiento farmacológico , Pirazoles/química , Bloqueadores de los Canales de Sodio/química , Canales de Sodio/química , Animales , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/uso terapéutico , Perros , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Actividad Motora/efectos de los fármacos , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Ratas , Bloqueadores de los Canales de Sodio/farmacocinética , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/metabolismoRESUMEN
A series of novel isoxazole voltage gated sodium channel blockers have been synthesized and evaluated. Substitutions on the benzylic position of benzamide were investigated to determine their effect on Na(v)1.7 inhibitory potency. The spirocyclobutyl substitution had the most significant enhancement on Na(v)1.7 inhibitory activity.
Asunto(s)
Isoxazoles/uso terapéutico , Dolor/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/metabolismo , Animales , Línea Celular , Enfermedad Crónica , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Dolor/inmunología , Ratas , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Nervios Espinales/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Analogs of the previously reported voltage gated sodium channel blocker CDA54 were prepared in which one of the amide functions was replaced with aromatic and non-aromatic heterocycles. Replacement of the amide with an aromatic heterocycle resulted in significant loss of sodium channel blocking activity, while non-aromatic heterocycle replacements were well tolerated.
Asunto(s)
Isoxazoles/química , Isoxazoles/farmacología , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Animales , Isoxazoles/uso terapéutico , Modelos Moleculares , Estructura Molecular , Dolor/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Bloqueadores de los Canales de Sodio/uso terapéutico , Nervios Espinales/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Cav2.2 channels play a critical role in pain signaling by controlling synaptic transmission between dorsal root ganglion neurons and dorsal horn neurons. The Cav2.2-selective peptide blocker ziconotide (Prialt, Elan Pharmaceuticals, Dublin, Ireland) has proven efficacious in pain relief, but has a poor therapeutic index and requires intrathecal administration. This has provided impetus for finding an orally active, state-dependent Cav2.2 inhibitor with an improved safety profile. Members of the Cav2 subfamily of calcium channels are the main contributors to central and peripheral synaptic transmission, but the pharmacological effects of blocking each subtype is not yet defined. Here we describe a high-throughput fluorescent assay using a fluorometric imaging plate reader (FLIPR [Molecular Devices, Sunnyvale, CA]) designed to quickly evaluate the state dependence and selectivity of inhibitors across the Cav2 subfamily. Stable cell lines expressing functional Cav2 channels (Ca(V)alpha, beta(3), and alpha(2)delta subunits) were co-transfected with an inward rectifier (Kir2.3) so that membrane potential, and therefore channel state, could be controlled by external potassium concentration. Following cell incubation in drug with varying concentrations of potassium, a high potassium trigger was added to elicit calcium influx through available, unblocked channels. State-dependent inhibitors that preferentially bind to channels in the open or inactivated state can be identified by their increased potency at higher potassium concentrations, where cells are depolarized and channels are biased towards these states. Although the Cav2 channel subtypes differ in their voltage dependence of inactivation, by adjusting pre-trigger potassium concentrations, the degree of steady-state inactivation can be more closely matched across Cav2 subtypes to assess molecular selectivity.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Caveolina 2/efectos de los fármacos , Caveolina 2/fisiología , Evaluación Preclínica de Medicamentos/métodos , Western Blotting , Calcio/metabolismo , Línea Celular , Electrofisiología , Humanos , Inmunohistoquímica , Potenciales de la Membrana/efectos de los fármacos , Técnicas de Placa-Clamp , Potasio/farmacología , Canales de Potasio de Rectificación Interna/efectos de los fármacos , Canales de Potasio de Rectificación Interna/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
A series of 3-amino-1,5-benzodiazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of this series displayed subnanomolar, state-dependent sodium channel block, and was orally efficacious in a mouse model of epilepsy.
Asunto(s)
Anticonvulsivantes/farmacología , Benzodiazepinonas/farmacología , Epilepsia/tratamiento farmacológico , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Bloqueadores de los Canales de Sodio/farmacología , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacocinética , Benzodiazepinonas/síntesis química , Benzodiazepinonas/farmacocinética , Electrofisiología , Electrochoque , Epilepsia/metabolismo , Canales de Potasio Éter-A-Go-Go/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Humanos , Ratones , Estructura Molecular , Ratas , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacocinéticaRESUMEN
A series of imidazopyridines were evaluated as potential sodium channel blockers for the treatment of neuropathic pain. Several members were identified with good hNa(v)1.7 potency and excellent rat pharmacokinetic profiles. Compound 4 had good efficacy (52% and 41% reversal of allodynia at 2 and 4h post-dose, respectively) in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain when dosed orally at 10mg/kg.
Asunto(s)
Piridinas/química , Piridinas/farmacología , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/metabolismo , Analgésicos/química , Analgésicos/farmacología , Animales , Inflamación/tratamiento farmacológico , Estructura Molecular , Canal de Sodio Activado por Voltaje NAV1.7 , Dolor/tratamiento farmacológico , Ratas , Bloqueadores de los Canales de Sodio/farmacocinética , Relación Estructura-ActividadRESUMEN
Delayed-rectifier K+ currents (I(DR)) in pancreatic beta-cells are thought to contribute to action potential repolarization and thereby modulate insulin secretion. The voltage-gated K+ channel, K(V)2.1, is expressed in beta-cells, and the biophysical characteristics of heterologously expressed channels are similar to those of I(DR) in rodent beta-cells. A novel peptidyl inhibitor of K(V)2.1/K(V)2.2 channels, guangxitoxin (GxTX)-1 (half-maximal concentration approximately 1 nmol/l), has been purified, characterized, and used to probe the contribution of these channels to beta-cell physiology. In mouse beta-cells, GxTX-1 inhibits 90% of I(DR) and, as for K(V)2.1, shifts the voltage dependence of channel activation to more depolarized potentials, a characteristic of gating-modifier peptides. GxTX-1 broadens the beta-cell action potential, enhances glucose-stimulated intracellular calcium oscillations, and enhances insulin secretion from mouse pancreatic islets in a glucose-dependent manner. These data point to a mechanism for specific enhancement of glucose-dependent insulin secretion by applying blockers of the beta-cell I(DR), which may provide advantages over currently used therapies for the treatment of type 2 diabetes.
Asunto(s)
Canales de Potasio de Tipo Rectificador Tardío/fisiología , Glucosa/farmacología , Insulina/metabolismo , Islotes Pancreáticos/fisiología , Bloqueadores de los Canales de Potasio/farmacología , Secuencia de Aminoácidos , Animales , Canales de Potasio de Tipo Rectificador Tardío/efectos de los fármacos , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Cinética , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones , Datos de Secuencia Molecular , Péptidos/química , Péptidos/farmacología , Bloqueadores de los Canales de Potasio/química , Venenos de Araña/química , Venenos de Araña/farmacologíaRESUMEN
The tarantula venom peptides ProTx-I and ProTx-II inhibit voltage-gated sodium channels by shifting their voltage dependence of activation to a more positive potential, thus acting by a mechanism similar to that of potassium channel gating modifiers such as hanatoxin and VSTX1. ProTx-I and ProTx-II inhibit all sodium channel (Nav1) subtypes tested with similar potency and represent the first potent peptidyl inhibitors of TTX-resistant sodium channels. Like gating modifiers of potassium channels, ProTx-I and ProTx-II conform to the inhibitory cystine knot motif, and ProTx-II was demonstrated to bind to sodium channels in the closed state. Both toxins have been synthesized chemically, and ProTx-II, produced by recombinant means, has been used to map the interaction surface of the peptide with the Nav1.5 channel. In comparison, beta-scorpion toxins activate sodium channels by shifting the voltage dependence of activation to more negative potentials, and together these peptides represent valuable tools for exploring the gating mechanism of sodium channels.
Asunto(s)
Activación del Canal Iónico , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/efectos de los fármacos , Venenos de Araña/farmacología , Animales , Humanos , Activación del Canal Iónico/efectos de los fármacos , Activación del Canal Iónico/fisiologíaRESUMEN
The discovery of the natural product nodulisporic acid A (NsA A) and its potent, systemic insecticidal activity at Merck Research Laboratories in 1992 stimulated intense scientific scrutiny. Interest in this new class of indole diterpenes led to extensive delineation of its properties, both chemical and biological. Synthetic modification of NsA A served to identify its pharmacologically permissive and non-permissive regions, produced semisynthetic derivatives with enhanced adulticidal flea efficacy (both in vitro and in vivo), and provided useful tools to support biological studies. Early observations in rodent models showed a wide therapeutic index for NsA A and detailed mechanism of action investigations demonstrated that it selectively modulated an invertebrate specific glutamate-gated ion channel for which no mammalian homolog exists. Consistent with these mechanistic conclusions, dogs treated orally with either NsA A or closely related amide analogs (15 mg/kg dosages) showed no apparent toxicity, and measurement of systemic flea efficacy in these animals demonstrated that prolonged antiparasitic activity was attained, up to 14 days subsequent to treatment with a single p.o. dose for fleas or up to 4 weeks for ticks. The extended flea efficacy was correlated to both the in vivo pharmacokinetic profile of a given analog and its intrinsic in vitro potency against fleas. In addition, studies directed towards the total synthesis of NsA A have been reported.
Asunto(s)
Infestaciones Ectoparasitarias/tratamiento farmacológico , Indoles/uso terapéutico , Animales , Canales de Cloruro/antagonistas & inhibidores , Perros , Infestaciones Ectoparasitarias/veterinaria , Indoles/administración & dosificación , Indoles/química , Estructura Molecular , Siphonaptera/efectos de los fármacos , Relación Estructura-Actividad , Garrapatas/efectos de los fármacosRESUMEN
The discovery of novel therapeutic agents that act on voltage-gated sodium channels requires the establishment of high-capacity screening assays that can reliably measure the activity of these proteins. Fluorescence resonance energy transfer (FRET) technology using membrane potential-sensitive dyes has been shown to provide a readout of voltage-gated sodium channel activity in stably transfected cell lines. Due to the inherent rapid inactivation of sodium channels, these assays require the presence of a channel activator to prolong channel opening. Because sodium channel activators and test compounds may share related binding sites on the protein, the assay protocol is critical for the proper identification of channel inhibitors. In this study, high throughput, functional assays for the voltage-gated sodium channels, hNa(V)1.5 and hNa(V)1.7, are described. In these assays, channels stably expressed in HEK cells are preincubated with test compound in physiological medium and then exposed to a sodium channel activator that slows channel inactivation. Sodium ion movement through open channels causes membrane depolarization that can be measured with a FRET dye membrane potential-sensing system, providing a large and reproducible signal. Unlike previous assays, the signal obtained in the agonist initiation assay is sensitive to all sodium channel modulators that were tested and can be used in high throughput mode, as well as in support of Medicinal Chemistry efforts for lead optimization.
Asunto(s)
Colorantes/análisis , Transferencia Resonante de Energía de Fluorescencia/métodos , Canales de Sodio/análisis , Canales de Sodio/fisiología , Línea Celular , Colorantes/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Proteínas Musculares/análisis , Proteínas Musculares/fisiología , Canal de Sodio Activado por Voltaje NAV1.5 , Canal de Sodio Activado por Voltaje NAV1.7 , Bloqueadores de los Canales de Sodio/farmacología , Veratridina/farmacologíaRESUMEN
We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Cav2.2 potency without the liability of the circulating sulfonamide metabolite.
RESUMEN
The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/química , Canales de Calcio Tipo N/fisiología , Dolor Crónico/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Piperidinas/farmacología , Sulfonamidas/farmacología , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacocinética , Canales de Calcio Tipo N/metabolismo , Células Cultivadas , Perros , Humanos , Ratones , Ratones Noqueados , Microsomas Hepáticos/efectos de los fármacos , Técnicas de Placa-Clamp , Piperidinas/síntesis química , Piperidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Distribución TisularRESUMEN
A series of benzodiazepines and benzazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of the benzazepinone series, compound 47, displayed potent, state-dependent block of hNa(v)1.7, and was orally efficacious in a rat model of neuropathic pain.